Cystatin C identifies chronic kidney disease patients at higher risk for complications. - Peralta, Carmen A; Katz, Ronit; Sarnak, Mark J; Ix, Joachim; Fried, Linda F; de Boer, Ian; Palmas, Walter; Siscovick, David; Levey, Andrew S; Shlipak, Michael G (J Am Soc Nephrol, 2011)
Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9% had CKD by the creatinine-based equation only, 2% had CKD by the cystatin C-based equation only, and 4% had CKD by both equations; in CHS, these percentages were 12, 4, and 13%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95% CI 0.98 to 1.21), 1.78 (95% CI 1.53 to 2.08), and 1.74 (95% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.
Keywords: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Chronic Disease; Creatinine; Cystatin C; Disease Progression; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Factors

Diabetes mellitus, fasting glucose, and risk of cause-specific death. - Rao Kondapally Seshasai, Sreenivasa; Kaptoge, Stephen; Thompson, Alexander; Di Angelantonio, Emanuele; Gao, Pei; Sarwar, Nadeem; Whincup, Peter H; Mukamal, Kenneth J; Gillum, Richard F; Holme, Ingar; Njølstad, Inger; Fletcher, Astrid; et al. (N Engl J Med, 2011)
BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).
Keywords: Blood Glucose; Cause of Death; Diabetes Mellitus; Female; Humans; Hyperglycemia; Life Expectancy; Male; Middle Aged; Risk; Survival Analysis

The effects of physical activity, education, and body mass index on the aging brain. - Ho, April J; Raji, Cyrus A; Becker, James T; Lopez, Oscar L; Kuller, Lewis H; Hua, Xue; Dinov, Ivo D; Stein, Jason L; Rosano, Caterina; Toga, Arthur W; Thompson, Paul M (Hum Brain Mapp, 2011)
Normal human aging is accompanied by progressive brain tissue loss and cognitive decline; however, several factors are thought to influence brain aging. We applied tensor-based morphometry to high-resolution brain MRI scans to determine whether educational level or physical activity was associated with brain tissue volumes in the elderly, particularly in regions susceptible to age-related atrophy. We mapped the 3D profile of brain volume differences in 226 healthy elderly subjects (130F/96M; 77.9 ± 3.6 SD years) from the Cardiovascular Health Study-Cognition Study. Statistical maps revealed the 3D profile of brain regions whose volumes were associated with educational level and physical activity (based on leisure-time energy expenditure). After controlling for age, sex, and physical activity, higher educational levels were associated with ~2-3% greater tissue volumes, on average, in the temporal lobe gray matter. After controlling for age, sex, and education, greater physical activity was associated with ~2-2.5% greater average tissue volumes in the white matter of the corona radiata extending into the parietal-occipital junction. Body mass index (BMI) was highly correlated with both education and physical activity, so we examined BMI as a contributing factor by including physical activity, education, and BMI in the same model; only BMI effects remained significant. This is one of the largest MRI studies of factors influencing structural brain aging, and BMI may be a key factor explaining the observed relationship between education, physical activity, and brain structure. Independent contributions to brain structure could not be teased apart as all these factors were highly correlated with one another.
Keywords: Aged; Aged, 80 and over; Aging; Analysis of Variance; Body Mass Index; Brain; Brain Mapping; Educational Status; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Motor Activity; Neuropsychological Tests; Statistics as Topic

Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. - Pasaniuc, Bogdan; Zaitlen, Noah; Lettre, Guillaume; Chen, Gary K; Tandon, Arti; Kao, W H Linda; Ruczinski, Ingo; Fornage, Myriam; Siscovick, David S; Zhu, Xiaofeng; Larkin, Emma; Lange, Leslie A; et al. (PLoS Genet, 2011)
While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.
Keywords: African Americans; Algorithms; Breast Neoplasms; Chromosome Mapping; Coronary Disease; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Variation; Genetics, Population; Genome, Human; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Male; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Principal Component Analysis; Receptor, Fibroblast Growth Factor, Type 2; Software

Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. - Thacker, Evan L; Psaty, Bruce M; McKnight, Barbara; Heckbert, Susan R; Longstreth, W T; Mukamal, Kenneth J; Meigs, James B; de Boer, Ian H; Boyko, Edward J; Carnethon, Mercedes R; Kizer, Jorge R; Tracy, Russell P; et al. (Stroke, 2011)
BACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults. METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance. RESULTS: Analyses included 3442 participants (42% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95% CI, 0.84-1.46). CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.
Keywords: Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Brain Ischemia; Fasting; Female; Humans; Incidence; Insulin Resistance; Male; Risk; Stroke

A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. - Taylor, Kira C; Lange, Leslie A; Zabaneh, Delilah; Lange, Ethan; Keating, Brendan J; Tang, Weihong; Smith, Nicholas L; Delaney, Joseph A; Kumari, Meena; Hingorani, Aroon; North, Kari E; Kivimaki, Mika; et al. (Hum Mol Genet, 2011)
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
Keywords: Adult; African Americans; Aged; Cardiovascular Diseases; European Continental Ancestry Group; Factor VII; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. - Liu, Ching-Ti; Garnaas, Maija K; Tin, Adrienne; Köttgen, Anna; Franceschini, Nora; Peralta, Carmen A; de Boer, Ian H; Lu, Xiaoning; Atkinson, Elizabeth; Ding, Jingzhong; Nalls, Michael; Shriner, Daniel; et al. (PLoS Genet, 2011)
Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Keywords: Adaptor Proteins, Vesicular Transport; Adult; African Continental Ancestry Group; Aged; Animals; Female; Gene Knockdown Techniques; Genetic Association Studies; Genetic Loci; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; KCNQ1 Potassium Channel; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Neoplasm Proteins; Phenotype; Polymorphism, Single Nucleotide; Zebrafish

Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. - Dumitrescu, Logan; Carty, Cara L; Taylor, Kira; Schumacher, Fredrick R; Hindorff, Lucia A; Ambite, José L; Anderson, Garnet; Best, Lyle G; Brown-Gentry, Kristin; Bůzková, Petra; Carlson, Christopher S; Cochran, Barbara; et al. (PLoS Genet, 2011)
For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Continental Population Groups; Female; Gene Frequency; Genetics, Population; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Molecular Epidemiology; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Triglycerides; Young Adult

Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. - Lemaitre, Rozenn N; Tanaka, Toshiko; Tang, Weihong; Manichaikul, Ani; Foy, Millennia; Kabagambe, Edmond K; Nettleton, Jennifer A; King, Irena B; Weng, Lu-Chen; Bhattacharya, Sayanti; Bandinelli, Stefania; Bis, Joshua C; et al. (PLoS Genet, 2011)
Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
Keywords: Alleles; Continental Population Groups; Fatty Acids, Omega-3; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Metabolic Networks and Pathways; Polymorphism, Single Nucleotide

Genetic predictors of fibrin D-dimer levels in healthy adults. - Smith, Nicholas L; Huffman, Jennifer E; Strachan, David P; Huang, Jie; Dehghan, Abbas; Trompet, Stella; Lopez, Lorna M; Shin, So-Youn; Baumert, Jens; Vitart, Veronique; Bis, Joshua C; Wild, Sarah H; et al. (Circulation, 2011)
BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
Keywords: Adult; Aged; Blood Coagulation; European Continental Ancestry Group; Factor V; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Genetic Testing; Genome-Wide Association Study; Humans; Male; Middle Aged; Reference Values; Thromboplastin

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. - Ehret, Georg B; Munroe, Patricia B; Rice, Kenneth M; Bochud, Murielle; Johnson, Andrew D; Chasman, Daniel I; Smith, Albert V; Tobin, Martin D; Verwoert, Germaine C; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; et al. (Nature, 2011)
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Keywords: Africa; Asia; Blood Pressure; Cardiovascular Diseases; Coronary Artery Disease; Europe; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypertension; Kidney Diseases; Polymorphism, Single Nucleotide; Stroke

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. - Schmidt, Helena; Zeginigg, Marion; Wiltgen, Marco; Freudenberger, Paul; Petrovic, Katja; Cavalieri, Margherita; Gider, Pierre; Enzinger, Christian; Fornage, Myriam; Debette, Stephanie; Rotter, Jerome I; Ikram, Mohammad A; et al. (Brain, 2011)
Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
Keywords: Aged; Aged, 80 and over; Alleles; Brain; Cerebral Small Vessel Diseases; Exons; Female; Follow-Up Studies; Genetic Association Studies; Genotype; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Phenotype; Promoter Regions, Genetic; Prospective Studies; Receptor, Notch3; Receptors, Notch

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. - Kilpeläinen, Tuomas O; Zillikens, M Carola; Stančáková, Alena; Finucane, Francis M; Ried, Janina S; Langenberg, Claudia; Zhang, Weihua; Beckmann, Jacques S; Luan, Jian'an; Vandenput, Liesbeth; Styrkarsdottir, Unnur; Zhou, Yanhua; et al. (Nat Genet, 2011)
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
Keywords: Adiponectin; Adiposity; Alleles; Body Fat Distribution; Body Mass Index; Body Weight; Female; Genetic Variation; Genome-Wide Association Study; Humans; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Meta-Analysis as Topic; Metabolome; Obesity; Polymorphism, Single Nucleotide; Subcutaneous Fat

Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. - Paré, Guillaume; Ridker, Paul M; Rose, Lynda; Barbalic, Maja; Dupuis, Josée; Dehghan, Abbas; Bis, Joshua C; Benjamin, Emelia J; Shiffman, Dov; Parker, Alexander N; Chasman, Daniel I (PLoS Genet, 2011)
Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.
Keywords: ABO Blood-Group System; Cohort Studies; Female; Gene Frequency; Genetic Loci; Genome, Human; Genome-Wide Association Study; Genotype; Humans; I-kappa B Kinase; Intercellular Adhesion Molecule-1; Lipase; Membrane Proteins; Models, Genetic; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Proteins; Transcription Factor RelA

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. - Soler Artigas, Maria; Loth, Daan W; Wain, Louise V; Gharib, Sina A; Obeidat, Ma'en; Tang, Wenbo; Zhai, Guangju; Zhao, Jing Hua; Smith, Albert Vernon; Huffman, Jennifer E; Albrecht, Eva; Jackson, Catherine M; et al. (Nat Genet, 2011)
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
Keywords: Child; European Continental Ancestry Group; Genome-Wide Association Study; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. - Fornage, Myriam; Debette, Stephanie; Bis, Joshua C; Schmidt, Helena; Ikram, M Arfan; Dufouil, Carole; Sigurdsson, Sigurdur; Lumley, Thomas; DeStefano, Anita L; Fazekas, Franz; Vrooman, Henri A; Shibata, Dean K; et al. (Ann Neurol, 2011)
OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
Keywords: Aged; Aged, 80 and over; Cerebral Cortex; Chromosomes, Human, Pair 17; Cognition Disorders; Cohort Studies; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Middle Aged; Movement Disorders; Nerve Fibers, Myelinated; Polymorphism, Single Nucleotide; Residence Characteristics; RNA, Messenger

A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. - Kaplan, Robert C; Petersen, Ann-Kristin; Chen, Ming-Huei; Teumer, Alexander; Glazer, Nicole L; Döring, Angela; Lam, Carolyn S P; Friedrich, Nele; Newman, Anne; Müller, Martina; Yang, Qiong; Homuth, Georg; et al. (Hum Mol Genet, 2011)
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
Keywords: Aged; Chromosomes, Human, Pair 7; Cohort Studies; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Polymorphism, Single Nucleotide

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. - Wain, Louise V; Verwoert, Germaine C; O'Reilly, Paul F; Shi, Gang; Johnson, Toby; Johnson, Andrew D; Bochud, Murielle; Rice, Kenneth M; Henneman, Peter; Smith, Albert V; Ehret, Georg B; Amin, Najaf; et al. (Nat Genet, 2011)
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Keywords: Arteries; Blood Pressure; Case-Control Studies; Follow-Up Studies; Genetic Loci; Genome-Wide Association Study; Humans; Hypertension; Linkage Disequilibrium; Polymorphism, Single Nucleotide

A genome-wide association study of aging. - Walter, Stefan; Atzmon, Gil; Demerath, Ellen W; Garcia, Melissa E; Kaplan, Robert C; Kumari, Meena; Lunetta, Kathryn L; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J; Völker, Uwe; Yu, Lei; et al. (Neurobiol Aging, 2011)
Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
Keywords: Aging; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Longevity

High blood pressure accelerates gait slowing in well-functioning older adults over 18-years of follow-up. - Rosano, Caterina; Longstreth, William T; Boudreau, Robert; Taylor, Christopher A; Du, Yan; Kuller, Lewis H; Newman, Anne B (J Am Geriatr Soc, 2011)
OBJECTIVES: To examine whether the association between hypertension and decline in gait speed is significant in well-functioning older adults and whether other health-related factors, such as brain, kidney, and heart function, can explain it. DESIGN: Longitudinal cohort study. SETTING: Cardiovascular Health Study. PARTICIPANTS: Of 2,733 potential participants with a brain magnetic resonance imaging (MRI) scan, measures of mobility and systolic blood pressure (BP), no self-reported disability in 1992 to 1994 (baseline), and with at least 1 follow-up gait speed measurement through 1997 to 1999, 643 (aged 73.6, 57% female, 15% black) who had received a second MRI in 1997 to 1999 and an additional gait speed measure in 2005 to 2006 were included. MEASUREMENTS: Mixed models with random slopes and intercepts were adjusted for age, race, and sex. Main explanatory factors included white matter hyperintensity progression, baseline cystatin-C, and left cardiac ventricular mass. Incidence of stroke and dementia, BP trajectories, and intake of antihypertensive medications during follow-up were tested as other potential explanatory factors. RESULTS: Higher systolic BP was associated with faster rate of gait speed decline in this selected group of 643 participants, and results were similar in the parent cohort (N = 2,733). Participants with high BP (n = 293) had a significantly faster rate of gait speed decline than those with baseline BP less than 140/90 mmHg and no history of hypertension (n = 350). Rates were similar for those with history of hypertension who were uncontrolled (n = 110) or controlled (n = 87) at baseline and for those who were newly diagnosed (n = 96) at baseline. Adjustment for explanatory factors or for other covariates (education, prevalent cardiovascular disease, physical activity, vision, mood, cognition, muscle strength, body mass index, osteoporosis) did not change the results. CONCLUSION: High BP accelerates gait slowing in well-functioning older adults over a long period of time, even for those who control their BP or develop hypertension later in life. Health-related measurements did not explain these associations. Future studies to investigate the mechanisms linking hypertension to slowing gait in older adults are warranted.
Keywords: Aged; Antihypertensive Agents; Comorbidity; Female; Follow-Up Studies; Gait; Geriatric Assessment; Humans; Hypertension; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors; Statistics, Nonparametric

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. - Arking, Dan E; Junttila, M Juhani; Goyette, Philippe; Huertas-Vazquez, Adriana; Eijgelsheim, Mark; Blom, Marieke T; Newton-Cheh, Christopher; Reinier, Kyndaron; Teodorescu, Carmen; Uy-Evanado, Audrey; Carter-Monroe, Naima; Kaikkonen, Kari S; et al. (PLoS Genet, 2011)
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
Keywords: Adult; Aged; Alleles; Chromosomes, Human, Pair 2; Death, Sudden, Cardiac; European Continental Ancestry Group; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Myocardial Contraction; Polymorphism, Single Nucleotide

Kidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2). - Peralta, Carmen A; Katz, Ronit; Shlipak, Michael; Dubin, Ruth; DeBoer, Ian; Jenny, Nancy; Fitzpatrick, Annette; Koro, Carol; Kestenbaum, Bryan; Ix, Joachim; Sarnak, Mark; Cushman, Mary (Am J Nephrol, 2011)
BACKGROUND: Whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with kidney function decline has not been well studied. METHODS: We investigated associations of Lp-PLA(2) antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m(2) per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m(2)). RESULTS: Mean age was 72 ± 5 years. Average eGFRcys decline was -1.79 ml/min/1.73 m(2) (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA(2) antigen, eGFRcys decline was faster among persons in the second, β -0.31 (95% CI -0.52, -0.10), third -0.19 (-0.41, 0.02) and fourth quartiles -0.26 (-0.48, -0.04) after full adjustment. Persons in the highest quartile of Lp-PLA(2) antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA(2) activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m(2)) at baseline. CONCLUSION: Higher levels of Lp-PLA(2) antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
Keywords: Aged; Cardiovascular Diseases; Creatinine; Cystatin C; Disease Progression; Female; Geriatrics; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Phospholipases A2; Risk Factors; Treatment Outcome

Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. - Schnabel, Renate B; Kerr, Kathleen F; Lubitz, Steven A; Alkylbekova, Ermeg L; Marcus, Gregory M; Sinner, Moritz F; Magnani, Jared W; Wolf, Philip A; Deo, Rajat; Lloyd-Jones, Donald M; Lunetta, Kathryn L; Mehra, Reena; et al. (Circ Cardiovasc Genet, 2011)
BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated. METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005). CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.
Keywords: African Americans; Aged; Alleles; Atrial Fibrillation; Chromosomes, Human, Pair 4; Cohort Studies; European Continental Ancestry Group; Female; Humans; Male; Middle Aged; National Heart, Lung, and Blood Institute (U.S.); Polymorphism, Single Nucleotide; Receptors, Interleukin-6; Risk Factors; Stroke; United States

Left ventricular ejection fraction assessment in older adults: an adjunct to natriuretic peptide testing to identify risk of new-onset heart failure and cardiovascular death? - deFilippi, Christopher R; Christenson, Robert H; Kop, Willem J; Gottdiener, John S; Zhan, Min; Seliger, Stephen L (J Am Coll Cardiol, 2011)
OBJECTIVES: The goal of this paper was to determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new-onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in older adults. BACKGROUND: Elevated NT-proBNP levels are common in older adults and are associated with increased risk of HF. METHODS: NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2 to 3 years later and echocardiography was repeated 5 years later (n = 2,375), with a median follow-up of 10.7 years. The addition of an abnormal (<55%) LVEF (n = 317 [7.7%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Changes in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF. RESULTS: For participants with a low baseline NT-proBNP level (<190 pg/ml; n = 2,918), addition of an abnormal LVEF did not improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (hazard ratio: 1.69 [95% confidence interval: 1.22 to 2.31]). Among those whose NT-proBNP subsequently increased ≥25% to ≥190 pg/ml, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP level (≥190 pg/ml) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF. CONCLUSIONS: Assessment of LVEF in HF-free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Death; Female; Follow-Up Studies; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Risk Factors; Stroke Volume; Survival Rate; Ventricular Function, Left

Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study. - Kizer, Jorge R; Arnold, Alice M; Jenny, Nancy S; Cushman, Mary; Strotmeyer, Elsa S; Ives, Diane G; Ding, Jingzhong; Kritchevsky, Stephen B; Chaves, Paulo H M; Hirsch, Calvin H; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2011)
BACKGROUND: Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined. METHODS: We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2-9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176). RESULTS: Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52-0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61-3.44] per SD for levels ≥20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78-4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20-2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67-3.67]) (p = .55), as compared with smaller changes for both. CONCLUSION: Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin-outcome associations reported previously.
Keywords: Adiponectin; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-6; Male; Mortality; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity; Survival Analysis; United States

Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. - Gansevoort, Ron T; Matsushita, Kunihiro; van der Velde, Marije; Astor, Brad C; Woodward, Mark; Levey, Andrew S; de Jong, Paul E; Coresh, Josef (Kidney Int, 2011)
Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.
Keywords: Aged; Albuminuria; Cohort Studies; Creatinine; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Proportional Hazards Models; Risk Factors

Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women. - Kizer, Jorge R; Biggs, Mary L; Ix, Joachim H; Mukamal, Kenneth J; Zieman, Susan J; de Boer, Ian H; Mozaffarian, Dariush; Barzilay, Joshua I; Strotmeyer, Elsa S; Luchsinger, José A; Elkind, Mitchell S V; Longstreth, W T; et al. (Am J Epidemiol, 2011)
The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥ 30 kg/m²) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m² was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.
Keywords: Adiposity; Age Factors; Aged; Aged, 80 and over; Brain Ischemia; Coronary Disease; Female; Humans; Incidence; Male; Middle Aged; Obesity; Prevalence; Retrospective Studies; Risk Factors; Sex Factors; United States

Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients. - Manning, Alisa K; LaValley, Michael; Liu, Ching-Ti; Rice, Kenneth; An, Ping; Liu, Yongmei; Miljkovic, Iva; Rasmussen-Torvik, Laura; Harris, Tamara B; Province, Michael A; Borecki, Ingrid B; Florez, Jose C; et al. (Genet Epidemiol, 2011)
INTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies. METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples. RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.
Keywords: Adult; Aged; Body Mass Index; Confidence Intervals; Diabetes Mellitus, Type 2; Environment; Fasting; Female; Genome, Human; Genome-Wide Association Study; Genotype; Humans; Insulin; Least-Squares Analysis; Male; Mathematical Computing; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide; PPAR gamma

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. - Bis, Joshua C; Kavousi, Maryam; Franceschini, Nora; Isaacs, Aaron; Abecasis, Goncalo R; Schminke, Ulf; Post, Wendy S; Smith, Albert V; Cupples, L Adrienne; Markus, Hugh S; Schmidt, Reinhold; Huffman, Jennifer E; et al. (Nat Genet, 2011)
Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
Keywords: Adult; Aged; Aging; Atherosclerosis; Carotid Intima-Media Thickness; Cohort Studies; Coronary Artery Disease; European Continental Ancestry Group; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Genotype; Heart; Humans; Middle Aged; Phenotype; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Risk Factors

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. - Dehghan, Abbas; Dupuis, Josée; Barbalic, Maja; Bis, Joshua C; Eiriksdottir, Gudny; Lu, Chen; Pellikka, Niina; Wallaschofski, Henri; Kettunen, Johannes; Henneman, Peter; Baumert, Jens; Strachan, David P; et al. (Circulation, 2011)
BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
Keywords: Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Risk Factors; Vasculitis

Mineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study. - Robinson-Cohen, Cassianne; Katz, Ronit; Hoofnagle, Andrew N; Cauley, Jane A; Furberg, Curt D; Robbins, John A; Chen, Zhao; Siscovick, David S; de Boer, Ian H; Kestenbaum, Bryan (J Clin Endocrinol Metab, 2011)
CONTEXT: Disturbances in mineral metabolism are associated with lower bone mineral density and fracture; however, previous human studies have assessed individual mineral metabolism markers in isolation. OBJECTIVE: We assessed serum concentrations of 25-hydroxyvitamin D (25-OHD), PTH, and bone-specific alkaline phosphatase (BAP) concentrations individually, and in combination, in association with the long-term risk of hip fracture among a general population of older adults. DESIGN AND SETTING: We studied 2294 participants from the Cardiovascular Health Study (mean age 74 yr) who were ambulatory and free of hip fracture and known cardiovascular disease at baseline. We used proportional hazards models to evaluate associations of baseline serum 25-OHD, PTH, and BAP concentrations with the time to first hospitalized hip fracture. RESULTS: During a median of 13 yr of follow-up, 242 participants (10.6%) developed an incident hip fracture. Serum 25-OHD concentrations less than 15 ng/ml were associated with a 61% greater adjusted risk of fracture (95% confidence interval 12-132% greater). In contrast, neither serum PTH nor BAP concentrations were significantly associated with fracture risk. The association of 25-OHD deficiency with hip fracture was not significantly altered by either PTH or BAP concentrations. CONCLUSIONS: Serum concentrations of 25-OHD, but not PTH or BAP, are associated with long-term hip fracture risk among ambulatory older adults. These data suggest that 25-OHD is the most relevant mineral metabolism marker of fracture risk among older people.
Keywords: Aged; Aged, 80 and over; Alkaline Phosphatase; Biomarkers; Bone Density; Female; Hip Fractures; Humans; Male; Parathyroid Hormone; Risk; Vitamin D

New gene functions in megakaryopoiesis and platelet formation. - Gieger, Christian; Radhakrishnan, Aparna; Cvejic, Ana; Tang, Weihong; Porcu, Eleonora; Pistis, Giorgio; Serbanovic-Canic, Jovana; Elling, Ulrich; Goodall, Alison H; Labrune, Yann; Lopez, Lorna M; Mägi, Reedik; et al. (Nature, 2011)
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
Keywords: Animals; Blood Platelets; Cell Size; Drosophila melanogaster; Drosophila Proteins; Europe; Gene Expression Profiling; Gene Silencing; Genome, Human; Genome-Wide Association Study; Hematopoiesis; Humans; Megakaryocytes; Platelet Count; Protein Interaction Maps; Transcription, Genetic; Zebrafish; Zebrafish Proteins

N-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study. - Patton, Kristen K; Sotoodehnia, Nona; DeFilippi, Christopher; Siscovick, David S; Gottdiener, John S; Kronmal, Richard A (Heart Rhythm, 2011)
BACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women. OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population. METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP. RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001). CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
Keywords: Age Distribution; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Confidence Intervals; Death, Sudden, Cardiac; Female; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sex Distribution; Time Factors; United States

Patterns and predictors of recovery from exhaustion in older adults: the cardiovascular health study. - Whitson, Heather E; Thielke, Stephen; Diehr, Paula; O'Hare, Ann M; Chaves, Paulo H M; Zakai, Neil A; Arnold, Alice; Chaudhry, Sarwat; Ives, Diane; Newman, Anne B (J Am Geriatr Soc, 2011)
OBJECTIVES: To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults. DESIGN: Secondary analysis of a cohort study. SETTING: Six annual examinations in four U.S. communities. PARTICIPANTS: Four thousand five hundred eighty-four men and women aged 69 and older. MEASUREMENTS: Exhaustion was considered present when a participant responded "a moderate amount" or "most of the time" to either of two questions: "How often have you had a hard time getting going?" and "How often does everything seem an effort?" RESULTS: Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion free at least once during follow-up. When data from all time points were considered, 48% of those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease. CONCLUSION: Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being.
Keywords: Aged; Aging; Cardiovascular Physiological Phenomena; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Geriatric Assessment; Health Status; Humans; Male; Predictive Value of Tests; Recovery of Function; Retrospective Studies; United States

Plasma omega-3 fatty acids and incident diabetes in older adults. - Djoussé, Luc; Biggs, Mary L; Lemaitre, Rozenn N; King, Irena B; Song, Xiaoling; Ix, Joachim H; Mukamal, Kenneth J; Siscovick, David S; Mozaffarian, Dariush (Am J Clin Nutr, 2011)
BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs. OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes. DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks. RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03). CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.
Keywords: Aged; Aged, 80 and over; alpha-Linolenic Acid; Diabetes Mellitus; Fatty Acids, Omega-3; Female; Humans; Male; Phospholipids; Proportional Hazards Models; Prospective Studies

Predictive value of depressive symptoms and B-type natriuretic peptide for new-onset heart failure and mortality. - van den Broek, Krista C; deFilippi, Christopher R; Christenson, Robert H; Seliger, Stephen L; Gottdiener, John S; Kop, Willem J (Am J Cardiol, 2011)
Depression and natriuretic peptides predict heart failure (HF) progression, but the unique contributions of depression and biomarkers associated with HF outcomes are not known. The present study determined the additive predictive value of depression and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) for new-onset HF in HF-free subjects and mortality in patients with HF. The participants in the Cardiovascular Health Study were assessed for depressive symptoms using the Center for Epidemiologic Studies Depression Scale and NT-proBNP using an electrochemiluminescence immunoassay. The validated cutoff values for depression (Center for Epidemiologic Studies Depression Scale ≥8) and NT-proBNP (≥190 pg/ml) were used. The risks of incident HF and mortality (cardiovascular disease-related and all-cause) were examined during a median follow-up of 11 years, adjusting for demographics, clinical factors, and health behaviors. In patients with HF (n = 208), depression was associated with an elevated risk of cardiovascular disease mortality (hazard ratios [HR] 2.07, 95% confidence interval [CI] 1.31 to 3.27) and all-cause mortality (HR 1.49, 95% CI 1.05 to 2.11), independent of the NT-proBNP level and covariates. The combined presence of depression and elevated NT-proBNP was associated with substantially elevated covariate-adjusted risks of cardiovascular disease mortality (HR 5.42, 95% CI 2.38 to 12.36) and all-cause mortality (HR 3.72, 95% CI 2.20 to 6.37). In the 4,114 HF-free subjects, new-onset HF was independently predicted by an elevated NT-proBNP level (HR 2.27, 95% CI 1.97 to 2.62) but not depression (HR 1.08, 95% CI 0.92 to 1.26) in covariate-adjusted analysis. In conclusion, depression and NT-proBNP displayed additive predictive value for mortality in patients with HF. These associations can be explained by complementary pathophysiologic mechanisms. The presence of both elevated depression and NT-proBNP levels might improve the identification of patients with HF with a high risk of mortality.
Keywords: Aged; Depression; Disease Progression; Female; Follow-Up Studies; Heart Failure; Humans; Incidence; Male; Natriuretic Peptide, Brain; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; United States

Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study. - Shoben, Abigail B; Kestenbaum, Bryan; Levin, Gregory; Hoofnagle, Andrew N; Psaty, Bruce M; Siscovick, David S; de Boer, Ian H (Am J Epidemiol, 2011)
Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.
Keywords: Aged; Biomarkers; Continental Population Groups; Exercise; Female; Humans; Male; Residence Characteristics; Seasons; Sex Factors; Vitamin D

Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. - Wormser, David; Kaptoge, Stephen; Di Angelantonio, Emanuele; Wood, Angela M; Pennells, Lisa; Thompson, Alex; Sarwar, Nadeem; Kizer, Jorge R; Lawlor, Debbie A; Nordestgaard, Børge G; Ridker, Paul; Salomaa, Veikko; et al. (Lancet, 2011)
BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease. METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios. RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70). INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids. FUNDING: British Heart Foundation and UK Medical Research Council.
Keywords: Age Factors; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Obesity, Abdominal; Proportional Hazards Models; Prospective Studies; Risk Assessment; Sex Factors; Smoking; Systole; Waist Circumference; Waist-Hip Ratio

Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. - de Boer, Ian H; Katz, Ronit; Chonchol, Michel; Ix, Joachim H; Sarnak, Mark J; Shlipak, Michael G; Siscovick, David S; Kestenbaum, Bryan (Clin J Am Soc Nephrol, 2011)
BACKGROUND AND OBJECTIVES: Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether "nutritional" forms of vitamin D affect GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested whether serum 25-hydroxyvitamin D concentration (25(OH)D), a measure of total vitamin D intake from cutaneous synthesis and dietary consumption, is associated with loss of estimated GFR among 1705 older adults with predominantly normal baseline kidney function participating in the Cardiovascular Health Study. Baseline 25(OH)D was measured by HPLC-tandem mass spectrometry. GFR was estimated at baseline and 4 years later using the CKD-EPI formula, with rapid GFR loss defined as 12 ml/min per 1.73 m(2) or more over 4 years. RESULTS: Rapid GFR loss was observed for 207 participants (12%). Each 10 ng/ml lower 25(OH)D was associated with a 25% greater risk of rapid GFR loss (95% confidence interval [CI] 5%, 49%, P = 0.01), adjusting for potential confounding characteristics. Compared with 25(OH)D ≥30 ng/ml, 25(OH)D concentrations 15 to 29 ng/ml and <15 ng/ml were associated with 29% (95% CI -13%, 91%) and 68% (95% CI 1%, 177%) greater adjusted risks of rapid GFR loss, respectively. Magnitudes of association were largest among participants with diabetes. RESULTS: were similar evaluating a composite outcome of rapid GFR loss, end stage renal disease, and death. Conclusions Insufficient 25(OH)D may be a modifiable risk factor for early GFR loss. We recommend clinical trials to determine whether vitamin D supplementation prevents the development and progression of CKD.
Keywords: Aged; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Prospective Studies; Vitamin D

Serum 25-hydroxyvitamin D and physical function in older adults: the Cardiovascular Health Study All Stars. - Houston, Denise K; Tooze, Janet A; Davis, Cralen C; Chaves, Paulo H M; Hirsch, Calvin H; Robbins, John A; Arnold, Alice M; Newman, Anne B; Kritchevsky, Stephen B (J Am Geriatr Soc, 2011)
OBJECTIVES: To examine the association between 25-hydroxyvitamin D (25(OH)D) and physical function in adults of advanced age. DESIGN: Cross-sectional and longitudinal analysis of physical function over 3 years of follow-up in the Cardiovascular Health Study All Stars. SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania. PARTICIPANTS: Community-dwelling adults aged 77 to 100 (N = 988). MEASUREMENTS: Serum 25-hydroxyvitamin D 25(OH)D), Short Physical Performance Battery (SPPB), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living (ADLs) disability were assessed at baseline and every 6 months over 3 years of follow-up. RESULTS: Almost one-third (30.8%) of participants were deficient in 25(OH)D (<20 ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53 (0.24)) than in those with sufficient 25(OH)D (≥30 ng/mL) (7.15 (0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P = .006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7 (0.6) kg vs 26.0 (0.6) kg, P = .02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR = 1.44, 95% confidence interval (CI)) = 0.96-2.14) and ADL disability (OR = 1.51, 95% CI = 1.01-2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3 years of follow-up (hazard ratio = 1.56, 95% CI = 1.06-2.30). CONCLUSION: Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community-dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Female; Follow-Up Studies; Geriatric Assessment; Health Surveys; Humans; Male; Mobility Limitation; Muscle Strength; Physical Fitness; Proportional Hazards Models; Reference Values; United States; Vitamin D; Vitamin D Deficiency

Subclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers. - Inzitari, Marco; Arnold, Alice M; Patel, Kushang V; Mercer, Laina D; Karlamangla, Arun; Ding, Jingzhong; Psaty, Bruce M; Williamson, Jeff D; Kuller, Lewis H; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2011)
BACKGROUND: Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. Methods and Results. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M ± SD 74.3 years ± 5.1, 63% women, 17% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification. CONCLUSIONS: Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cost of Illness; Female; Humans; Male; Risk; Vascular Diseases

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. - Kanoni, Stavroula; Nettleton, Jennifer A; Hivert, Marie-France; Ye, Zheng; van Rooij, Frank J A; Shungin, Dmitry; Sonestedt, Emily; Ngwa, Julius S; Wojczynski, Mary K; Lemaitre, Rozenn N; Gustafsson, Stefan; Anderson, Jennifer S; et al. (Diabetes, 2011)
OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
Keywords: Blood Glucose; Cation Transport Proteins; Cohort Studies; Humans; Polymorphism, Single Nucleotide; Zinc; Zinc Transporter 8

Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. - Emanuel, James E; Lopez, Oscar L; Houck, Patricia R; Becker, James T; Weamer, Elise A; Demichele-Sweet, Mary Ann A; Kuller, Lewis; Sweet, Robert A (Am J Geriatr Psychiatry, 2011)
OBJECTIVE: To compare the trajectories of cognitive decline between groups with, and without, the later development of psychotic symptoms during Alzheimer disease (AD) or mild cognitive impairment (MCI). DESIGN: : The authors examined cognitive function in a new analysis of an existing data set, the Cardiovascular Health Study, an epidemiologic, longitudinal follow-up study. Our analyses examined 9 years of follow-up data. SETTING: Community. PARTICIPANTS: The authors examined subjects who were without dementia at study entry, received a diagnosis of AD or MCI during follow-up, and had been rated on the Neuropsychiatric Inventory for the presence of psychosis; 362 participants for the modified Mini-Mental State Examination (3MS) analysis and 350 participants for the digit symbol substitution test (DSST) analysis had sufficient follow-up data and apolipoprotein-∊ (APOE) genotyping. MEASUREMENTS: The 3MS and DSST were administered annually and analyzed using mixed-effects models including APOE4 status. RESULTS: : Mean 3MS and DSST scores did not differ between AD with psychosis (AD + P) and without psychosis groups at baseline. The 3MS and DSST scores decreased more rapidly in subjects who ultimately developed psychosis. CONCLUSIONS: Individuals who ultimately develop psychosis have more rapid cognitive deterioration during the earliest phases of AD than individuals with AD not developing psychosis. The genetic and other neurobiologic factors leading to the expression of AD + P may exert their effects by acceleration of the neurodegenerative process.
Keywords: Aged; Alzheimer Disease; Chi-Square Distribution; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Time Factors

Vitamin D, parathyroid hormone, and cardiovascular events among older adults. - Kestenbaum, Bryan; Katz, Ronit; de Boer, Ian; Hoofnagle, Andy; Sarnak, Mark J; Shlipak, Michael G; Jenny, Nancy S; Siscovick, David S (J Am Coll Cardiol, 2011)
OBJECTIVES: The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study). BACKGROUND: Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health. METHODS: A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality. RESULTS: There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events. CONCLUSIONS: Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Parathyroid Hormone; Prospective Studies; Vitamin D

Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study. - Deo, Rajat; Katz, Ronit; Shlipak, Michael G; Sotoodehnia, Nona; Psaty, Bruce M; Sarnak, Mark J; Fried, Linda F; Chonchol, Michel; de Boer, Ian H; Enquobahrie, Daniel; Siscovick, David; Kestenbaum, Bryan (Hypertension, 2011)
Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH ≥65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
Keywords: Aged; Cardiovascular Diseases; Comorbidity; Death, Sudden, Cardiac; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Kidney; Male; Middle Aged; Minerals; Parathyroid Hormone; Proportional Hazards Models; Risk Factors; Socioeconomic Factors; United States; Vitamin D

Adiposity and incident heart failure in older adults: the cardiovascular health study. - Djoussé, Luc; Bartz, Traci M; Ix, Joachim H; Zieman, Susan J; Delaney, Joseph A; Mukamal, Kenneth J; Gottdiener, John S; Siscovick, David S; Kizer, Jorge R (Obesity (Silver Spring), 2012)
While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident HF in older adults. We sought to examine the association between waist circumference (WC) and incident HF and assess whether sex modifies the relation between WC and HF. Prospective study using data on 4,861 participants of the Cardiovascular Health Study (1989-2007). HF was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio (HR). The mean age was 73.0 years for men and 72.3 years for women; 42.5% were men and 15.3% were African Americans. WC was positively associated with an increased risk of HF: each standard deviation of WC was associated with a 14% increased risk of HF (95% CI: 3%-26%) in a multivariable model. There was not a statistically significant sex-by-WC interaction (P = 0.081). BMI was positively associated with incident HF (HR: 1.22 (95% CI: 1.15-1.29) per standard deviation increase of BMI); however, this association was attenuated and became nonstatistically significant upon additional adjustment for WC (HR: 1.09 (95% CI: 0.99-1.21)). In conclusion, a higher WC is associated with an increased risk of HF independent of BMI in community-living older men and women.
Keywords: Adiposity; Aged; Aging; Body Fat Distribution; Body Mass Index; Female; Heart Failure; Humans; Incidence; Independent Living; Male; Obesity; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors; United States; Waist Circumference

Apolipoprotein E and kidney function in older adults. - Seshasai, Rebecca Kurnik; Katz, Ronit; de Boer, Ian H; Siscovick, David; Shlipak, Michael G; Rifkin, Dena E; Sarnak, Mark J (Clin Nephrol, 2012)
BACKGROUND: Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS). METHODS: Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2. RESULTS: Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 - 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 - 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression. CONCLUSIONS: The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
Keywords: Aged; Aged, 80 and over; Alleles; Apolipoproteins E; Confidence Intervals; Creatinine; Cross-Sectional Studies; Cystatin C; Disease Progression; European Continental Ancestry Group; Female; Gene Frequency; Genotype; Glomerular Filtration Rate; Humans; Kidney; Male; Odds Ratio; Renal Insufficiency, Chronic; Risk Factors

Assessment of gene-by-sex interaction effect on bone mineral density. - Liu, Ching-Ti; Estrada, Karol; Yerges-Armstrong, Laura M; Amin, Najaf; Evangelou, Evangelos; Li, Guo; Minster, Ryan L; Carless, Melanie A; Kammerer, Candace M; Oei, Ling; Zhou, Yanhua; Alonso, Nerea; et al. (J Bone Miner Res, 2012)
Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
Keywords: Bone Density; Cohort Studies; Female; Genes; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Reproducibility of Results; Sex Characteristics

Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. - Murabito, Joanne M; White, Charles C; Kavousi, Maryam; Sun, Yan V; Feitosa, Mary F; Nambi, Vijay; Lamina, Claudia; Schillert, Arne; Coassin, Stefan; Bis, Joshua C; Broer, Linda; Crawford, Dana C; et al. (Circ Cardiovasc Genet, 2012)
BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026). CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Ankle Brachial Index; Chromosomes, Human, Pair 9; Cohort Studies; Cyclin-Dependent Kinase Inhibitor p15; Female; Genome-Wide Association Study; Genotype; HapMap Project; Humans; Logistic Models; Male; Middle Aged; Peripheral Vascular Diseases; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Sex Factors

The association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons. - de Hollander, Ellen L; Bemelmans, Wanda Je; Boshuizen, Hendriek C; Friedrich, Nele; Wallaschofski, Henri; Guallar-Castillón, Pilar; Walter, Stefan; Zillikens, M Carola; Rosengren, Annika; Lissner, Lauren; Bassett, Julie K; Giles, Graham G; et al. (Int J Epidemiol, 2012)
BACKGROUND: For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined. METHODS: Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC-BMI categories and continuous WC (including WC and WC(2)) were calculated by the investigators and pooled by means of random-effects models. RESULTS: During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: ≥102 cm, women: ≥88 cm) was associated with increased all-cause mortality RRs for those in the 'healthy' weight {1.7 [95% confidence interval (CI): 1.2-2.2], 1.7 (95% CI: 1.3-2.3)}, overweight [1.1(95% CI: 1.0-1.3), 1.4 (95%: 1.1-1.7)] and obese [1.1 (95% CI: 1.0-1.3), 1.6 (95% CI: 1.3-1.9)] BMI category compared with the 'healthy' weight (20-24.9 kg/m(2)) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95% CI: 1.8-2.8)] and women [2.3 (95% CI: 1.8-3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women. CONCLUSIONS: Our results showed increased mortality risks for elderly people with an increased WC-even across BMI categories- and for those who were classified as 'underweight' using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.
Keywords: Aged; Body Mass Index; Body Weight; Cardiovascular Diseases; Female; Humans; Male; Mortality; Neoplasms; Overweight; Respiratory Tract Diseases; Risk Assessment; Waist Circumference

Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. - Ix, Joachim H; Biggs, Mary L; Mukamal, Kenneth J; Kizer, Jorge R; Zieman, Susan J; Siscovick, David S; Mozzaffarian, Dariush; Jensen, Majken K; Nelson, Lauren; Ruderman, Neil; Djoussé, Luc (Circulation, 2012)
BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD). METHODS AND RESULTS: Among 3710 community-living individuals ≥ 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01). CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those ≥ 75 years of age.
Keywords: African Continental Ancestry Group; Age Distribution; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Female; Humans; Incidence; Life Style; Lipids; Male; Pilot Projects; Prevalence; Proportional Hazards Models; Residence Characteristics; Risk Factors; Sex Distribution

Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe). - Patel, Sanjay R; Goodloe, Robert; De, Gourab; Kowgier, Matthew; Weng, Jia; Buxbaum, Sarah G; Cade, Brian; Fulop, Tibor; Gharib, Sina A; Gottlieb, Daniel J; Hillman, David; Larkin, Emma K; et al. (PLoS One, 2012)
Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10(-6). Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.
Keywords: Adult; African Americans; Aged; Alleles; European Continental Ancestry Group; Female; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Polysomnography; Sleep Apnea, Obstructive

Association of weight status with mortality in adults with incident diabetes. - Carnethon, Mercedes R; De Chavez, Peter John D; Biggs, Mary L; Lewis, Cora E; Pankow, James S; Bertoni, Alain G; Golden, Sherita H; Liu, Kiang; Mukamal, Kenneth J; Campbell-Jenkins, Brenda; Dyer, Alan R (JAMA, 2012)
CONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences. OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality. DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater. MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality. RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively. CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.
Keywords: Adult; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Female; Humans; Longitudinal Studies; Male; Middle Aged; Obesity; Overweight; United States

Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. - Fox, Caroline S; Matsushita, Kunihiro; Woodward, Mark; Bilo, Henk J G; Chalmers, John; Heerspink, Hiddo J Lambers; Lee, Brian J; Perkins, Robert M; Rossing, Peter; Sairenchi, Toshimi; Tonelli, Marcello; Vassalotti, Joseph A; et al. (Lancet, 2012)
BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown. METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes. FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts. INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes. FUNDING: US National Kidney Foundation.
Keywords: Aged; Albuminuria; Cardiovascular Diseases; Cause of Death; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Risk Factors

Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study. - Kizer, Jorge R; Benkeser, David; Arnold, Alice M; Mukamal, Kenneth J; Ix, Joachim H; Zieman, Susan J; Siscovick, David S; Tracy, Russell P; Mantzoros, Christos S; deFilippi, Christopher R; Newman, Anne B; Djoussé, Luc (Circulation, 2012)
BACKGROUND: Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk). METHODS AND RESULTS: In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality. CONCLUSIONS: Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.
Keywords: Adiponectin; Aged; Aged, 80 and over; Body Mass Index; Cardiovascular Diseases; Female; Health Surveys; Humans; Male; Molecular Weight

Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure. - Kop, Willem J; Gottdiener, John S; deFilippi, Christopher R; Barasch, Eddy; Seliger, Stephen L; Jenny, Nancy S; Christenson, Robert H (Circ Heart Fail, 2012)
BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Chi-Square Distribution; Collagen; Collagen Type I; Female; Fibrosis; Heart Failure; Humans; Linear Models; Longitudinal Studies; Male; Multivariate Analysis; Myocardium; Peptide Fragments; Peptides; Predictive Value of Tests; Procollagen; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Troponin T; Up-Regulation

Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. - Lorenz, Matthias W; Polak, Joseph F; Kavousi, Maryam; Mathiesen, Ellisiv B; Völzke, Henry; Tuomainen, Tomi-Pekka; Sander, Dirk; Plichart, Matthieu; Catapano, Alberico L; Robertson, Christine M; Kiechl, Stefan; Rundek, Tatjana; et al. (Lancet, 2012)
BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02). INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING: Deutsche Forschungsgemeinschaft.
Keywords: Cardiovascular Diseases; Carotid Intima-Media Thickness; Disease Progression; Follow-Up Studies; Humans; Myocardial Infarction; Prognosis; Risk Assessment; Stroke

Chronic kidney disease, insulin resistance, and incident diabetes in older adults. - Pham, Hien; Robinson-Cohen, Cassianne; Biggs, Mary L; Ix, Joachim H; Mukamal, Kenneth J; Fried, Linda F; Kestenbaum, Bryan; Siscovick, David S; de Boer, Ian H (Clin J Am Soc Nephrol, 2012)
BACKGROUND AND OBJECTIVES: Insulin resistance is a complication of advanced CKD. Insulin resistance is less well characterized in earlier stages of CKD. The response of the pancreatic β cell, effects on glucose tolerance, and risk of diabetes are not clear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Health Study included 4680 adults without baseline diabetes. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation was used to obtain the estimated GFR (eGFR). Insulin resistance was evaluated as fasting insulin concentration. The insulin sensitivity index, β cell function, and glucose tolerance were assessed by oral glucose tolerance testing. Incident diabetes was defined as fasting glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or use of glucose-lowering medications. RESULTS: Mean age was 72.5 years (range, 65-98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m(2). After adjustment, each 10 ml/min per 1.73 m(2) lower eGFR was associated with a 2.2% higher fasting insulin concentration (95% confidence interval [CI], 1.4%, 2.9%; P<0.001) and a 1.1% lower insulin sensitivity index (95% CI, 0.03%, 2.2%; P=0.04). Surprisingly, eGFR was associated with an augmented β cell function index (P<0.001), lower 2-hour glucose concentration (P=0.002), and decreased risk of glucose intolerance (P=0.006). Over a median 12 years' follow-up, 437 participants (9.3%) developed diabetes. eGFR was not associated with the risk of incident diabetes. CONCLUSIONS: Among older adults, lower eGFR was associated with insulin resistance. However, with lower eGFR, β cell function was appropriately augmented and risks of impaired glucose tolerance and incident diabetes were not increased.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Creatinine; Diabetes Mellitus; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Health Surveys; Humans; Hypoglycemic Agents; Incidence; Insulin; Insulin Resistance; Insulin-Secreting Cells; Kidney; Kidney Diseases; Linear Models; Male; Proportional Hazards Models; Risk Assessment; Risk Factors; United States

Circulating and dietary α-linolenic acid and incidence of congestive heart failure in older adults: the Cardiovascular Health Study. - Lemaitre, Rozenn N; Sitlani, Colleen; Song, Xiaoling; King, Irena B; McKnight, Barbara; Spiegelman, Donna; Sacks, Frank M; Djoussé, Luc; Rimm, Eric B; Siscovick, David S; Mozaffarian, Dariush (Am J Clin Nutr, 2012)
BACKGROUND: Few studies have evaluated the association between the n-3 fatty acid α-linolenic acid (ALA) and the incidence of congestive heart failure (CHF). OBJECTIVE: We investigated whether plasma phospholipid concentrations and estimated dietary consumption of ALA are associated with incident CHF. DESIGN: We used data from the Cardiovascular Health Study, a prospective cohort study of cardiovascular diseases among adults aged ≥65 y, from 4 US communities. A total of 2957 participants free of prevalent heart disease and with available fatty acid measurements were included in biomarker analyses (30,722 person-years and 686 incident CHF events). A total of 4432 participants free of prevalent heart disease were included in dietary analyses (52,609 person-years and 1072 events). We investigated the association of ALA with incident CHF by using Cox regression. RESULTS: After adjustment for age, sex, race, education, smoking status, BMI, waist circumference, and alcohol consumption, plasma phospholipid ALA was not associated with incident CHF (HR for the highest compared with the lowest quartile: 0.97; 95% CI: 0.79, 1.21; P-trend = 0.85). Likewise, dietary ALA was not associated with incident CHF (adjusted HR for the highest compared with the lowest quartile: 0.96; 95% CI: 0.82, 1.20; P-trend = 0.97). We observed no association of biomarker or dietary ALA with nonvalvular CHF subtype. We also found little evidence of an association between ALA and CHF in subgroups based on age, sex, diabetes, fish consumption, BMI, or FADS2 genotype (rs1535). CONCLUSION: ALA intake is not associated with incident CHF in older adults. This trial was registered at clinicaltrials.gov as NCT00005133.
Keywords: Aged; Alcohol Drinking; alpha-Linolenic Acid; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diet; Fatty Acid Desaturases; Female; Follow-Up Studies; Heart Failure; Humans; Incidence; Male; Polymorphism, Single Nucleotide; Prevalence; Prospective Studies; Risk Factors; Smoking; Surveys and Questionnaires; United States

Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. - Walford, G A; Green, T; Neale, B; Isakova, T; Rotter, J I; Grant, S F A; Fox, C S; Pankow, J S; Wilson, J G; Meigs, J B; Siscovick, D S; Bowden, D W; et al. (Diabetologia, 2012)
AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.
Keywords: Adult; Aged; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Disease Progression; Fasting; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Models, Genetic; Polymorphism, Single Nucleotide; Proportional Hazards Models; Regression Analysis; Risk

Comparing years of healthy life, measured in 16 ways, for normal weight and overweight older adults. - Diehr, Paula; Thielke, Stephen; O'Meara, Ellen; Fitzpatrick, Annette L; Newman, Anne (J Obes, 2012)
Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The "Overweight paradox" appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.

Echocardiography, natriuretic peptides, and risk for incident heart failure in older adults: the Cardiovascular Health Study. - Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V; deFilippi, Christopher R; Gottdiener, John S; Butler, Javed (JACC Cardiovasc Imaging, 2012)
OBJECTIVES: This study sought to examine the potential utility of echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for heart failure (HF) risk stratification in concert with a validated clinical HF risk score in older adults. BACKGROUND: Without clinical guidance, echocardiography and natriuretic peptides have suboptimal test characteristics for population-wide HF risk stratification. However, the value of these tests has not been examined in concert with a clinical HF risk score. METHODS: We evaluated the improvement in 5-year HF risk prediction offered by adding an echocardiographic score and/or NT-proBNP levels to the clinical Health Aging and Body Composition (ABC) HF risk score (base model) in 3,752 participants of the CHS (Cardiovascular Health Study) (age 72.6 ± 5.4 years; 40.8% men; 86.5% white). The echocardiographic score was derived as the weighted sum of independent echocardiographic predictors of HF. We assessed changes in Bayesian information criterion (BIC), C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). We examined also the weighted NRI across baseline HF risk categories under multiple scenarios of event versus nonevent weighting. RESULTS: Reduced left ventricular ejection fraction, abnormal E/A ratio, enlarged left atrium, and increased left ventricular mass were independent echocardiographic predictors of HF. Adding the echocardiographic score and NT-proBNP levels to the clinical model improved BIC (echocardiography: -43, NT-proBNP: -64.1, combined: -68.9; all p < 0.001) and C index (baseline: 0.746; echocardiography: +0.031, NT-proBNP: +0.027, combined: +0.043; all p < 0.01), and yielded robust IDI (echocardiography: 43.3%, NT-proBNP: 42.2%, combined: 61.7%; all p < 0.001), and NRI (based on Health ABC HF risk groups; echocardiography: 11.3%; NT-proBNP: 10.6%, combined: 16.3%; all p < 0.01). Participants at intermediate risk by the clinical model (5% to 20% 5-yr HF risk; 35.7% of the cohort) derived the most reclassification benefit. Echocardiography yielded modest reclassification when used sequentially after NT-proBNP. CONCLUSIONS: In older adults, echocardiography and NT-proBNP offer significant HF risk reclassification over a clinical prediction model, especially for intermediate-risk individuals.
Keywords: Aged; Biomarkers; Cardiomegaly; Echocardiography; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Risk; Risk Assessment; Ventricular Function, Left

Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. - Sweet, Robert A; Seltman, Howard; Emanuel, James E; Lopez, Oscar L; Becker, James T; Bis, Joshua C; Weamer, Elise A; Demichele-Sweet, Mary Ann A; Kuller, Lewis H (Am J Psychiatry, 2012)
OBJECTIVE: The trajectory of cognitive decline in patients with late-onset Alzheimer's disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer's disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease. METHOD: The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model's ability to detect the previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study's end. RESULTS: The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model's utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors. CONCLUSIONS: Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer's disease.
Keywords: Age of Onset; Aged; Alleles; Alzheimer Disease; Apolipoprotein E4; Bayes Theorem; Clusterin; Cohort Studies; Dementia; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Male; Models, Psychological; Monomeric Clathrin Assembly Proteins; Polymorphism, Single Nucleotide; Receptors, Complement 3b; Risk Factors

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. - Grallert, Harald; Dupuis, Josée; Bis, Joshua C; Dehghan, Abbas; Barbalic, Maja; Baumert, Jens; Lu, Chen; Smith, Nicholas L; Uitterlinden, André G; Roberts, Robert; Khuseyinova, Natalie; Schnabel, Renate B; et al. (Eur Heart J, 2012)
AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Coronary Artery Disease; Coronary Disease; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Middle Aged; Phospholipases A2; Polymorphism, Single Nucleotide

Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. - Buyske, Steven; Wu, Ying; Carty, Cara L; Cheng, Iona; Assimes, Themistocles L; Dumitrescu, Logan; Hindorff, Lucia A; Mitchell, Sabrina; Ambite, Jose Luis; Boerwinkle, Eric; Bůzková, Petra; Carlson, Chris S; et al. (PLoS One, 2012)
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
Keywords: African Americans; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Chromosomes, Human; Cohort Studies; Gene Frequency; Genome-Wide Association Study; Genotype; Humans; Metabolic Diseases; Polymorphism, Single Nucleotide; Quantitative Trait Loci

Evolution and functional impact of rare coding variation from deep sequencing of human exomes. - Tennessen, Jacob A; Bigham, Abigail W; O'Connor, Timothy D; Fu, Wenqing; Kenny, Eimear E; Gravel, Simon; McGee, Sean; Do, Ron; Liu, Xiaoming; Jun, Goo; Kang, Hyun Min; Jordan, Daniel; et al. (Science, 2012)
As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.
Keywords: African Americans; Disease; European Continental Ancestry Group; Evolution, Molecular; Exome; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; High-Throughput Nucleotide Sequencing; Humans; Male; Polymorphism, Single Nucleotide; Population Growth; Selection, Genetic

Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). - Ix, Joachim H; Katz, Ronit; Kestenbaum, Bryan R; de Boer, Ian H; Chonchol, Michel; Mukamal, Kenneth J; Rifkin, Dena; Siscovick, David S; Sarnak, Mark J; Shlipak, Michael G (J Am Coll Cardiol, 2012)
OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting. BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown. METHODS: Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status. RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45). CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.
Keywords: Aged; Aged, 80 and over; Biomarkers; Female; Fibroblast Growth Factors; Heart Failure; Humans; Kidney Function Tests; Male; Mortality; Renal Insufficiency, Chronic; United States

Fine-mapping and initial characterization of QT interval loci in African Americans. - Avery, Christy L; Sethupathy, Praveen; Buyske, Steven; He, Qianchuan; Lin, Dan-Yu; Arking, Dan E; Carty, Cara L; Duggan, David; Fesinmeyer, Megan D; Hindorff, Lucia A; Jeff, Janina M; Klein, Liviu; et al. (PLoS Genet, 2012)
The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
Keywords: African Americans; Aged; Computational Biology; Electrocardiography; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Male; Metagenomics; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Risk Factors; Tachycardia; United States

FTO genotype is associated with phenotypic variability of body mass index. - Yang, Jian; Loos, Ruth J F; Powell, Joseph E; Medland, Sarah E; Speliotes, Elizabeth K; Chasman, Daniel I; Rose, Lynda M; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Mägi, Reedik; Waite, Lindsay; Smith, Albert Vernon; et al. (Nature, 2012)
There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Keywords: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Height; Body Mass Index; Co-Repressor Proteins; Female; Genetic Variation; Genome-Wide Association Study; Humans; Male; Nerve Tissue Proteins; Phenotype; Polymorphism, Single Nucleotide; Proteins; Repressor Proteins

Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. - Wassel, Christina L; Lamina, Claudia; Nambi, Vijay; Coassin, Stefan; Mukamal, Kenneth J; Ganesh, Santhi K; Jacobs, David R; Franceschini, Nora; Papanicolaou, George J; Gibson, Quince; Yanek, Lisa R; van der Harst, Pim; et al. (Atherosclerosis, 2012)
BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance. RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
Keywords: Adult; African Americans; Aged; Ankle Brachial Index; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2B6; European Continental Ancestry Group; Female; Humans; Male; Middle Aged; Oxidoreductases, N-Demethylating; Peripheral Arterial Disease; Polymorphism, Single Nucleotide; Risk Factors; Transcription Factor 7-Like 2 Protein

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. - Traylor, Matthew; Farrall, Martin; Holliday, Elizabeth G; Sudlow, Cathie; Hopewell, Jemma C; Cheng, Yu-Ching; Fornage, Myriam; Ikram, M Arfan; Malik, Rainer; Bevan, Steve; Thorsteinsdottir, Unnur; Nalls, Mike A; et al. (Lancet Neurol, 2012)
BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort. INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
Keywords: Brain Ischemia; Databases, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Risk Factors; Stroke

Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. - Levin, Gregory P; Robinson-Cohen, Cassianne; de Boer, Ian H; Houston, Denise K; Lohman, Kurt; Liu, Yongmei; Kritchevsky, Stephen B; Cauley, Jane A; Tanaka, Toshiko; Ferrucci, Luigi; Bandinelli, Stefania; Patel, Kushang V; et al. (JAMA, 2012)
CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
Keywords: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Aged; Chronic Disease; Cohort Studies; Female; Genetic Variation; Genotype; Hip Fractures; Humans; Low Density Lipoprotein Receptor-Related Protein-2; Male; Meta-Analysis as Topic; Myocardial Infarction; Neoplasms; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Receptors, Cell Surface; Risk; Steroid Hydroxylases; Vitamin D; Vitamin D3 24-Hydroxylase

Genetic variants in Arhgef11 are associated with kidney injury in the Dahl salt-sensitive rat. - Williams, Jan M; Johnson, Ashley C; Stelloh, Cary; Dreisbach, Albert W; Franceschini, Nora; Regner, Kevin R; Townsend, Raymond R; Roman, Richard J; Garrett, Michael R (Hypertension, 2012)
A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to <375 kb on the basis of congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 single nucleotide polymorphisms (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only a few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.
Keywords: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Animals, Congenic; Blood Pressure; Blotting, Western; Chromosome Mapping; Gene Expression Profiling; Genetic Predisposition to Disease; Guanine Nucleotide Exchange Factors; Humans; Kidney; Kidney Diseases; Male; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Proteinuria; Quantitative Trait Loci; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Renal Circulation; Reverse Transcriptase Polymerase Chain Reaction; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction

Genome-wide association and functional follow-up reveals new loci for kidney function. - Pattaro, Cristian; Köttgen, Anna; Teumer, Alexander; Garnaas, Maija; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; et al. (PLoS Genet, 2012)
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Keywords: African Americans; Aged; Animals; Caspase 9; Cyclin-Dependent Kinases; DEAD-box RNA Helicases; DNA Helicases; European Continental Ancestry Group; Female; Follow-Up Studies; Gene Knockdown Techniques; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Phosphoric Diester Hydrolases; Zebrafish

Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. - Wilk, Jemma B; Shrine, Nick R G; Loehr, Laura R; Zhao, Jing Hua; Manichaikul, Ani; Lopez, Lorna M; Smith, Albert Vernon; Heckbert, Susan R; Smolonska, Joanna; Tang, Wenbo; Loth, Daan W; Curjuric, Ivan; et al. (Am J Respir Crit Care Med, 2012)
RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
Keywords: Aged; Female; Forced Expiratory Volume; Genome-Wide Association Study; Humans; Male; Middle Aged; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Receptors, Nicotinic; Receptors, Serotonin, 5-HT4; Smoking; Vital Capacity

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. - Huang, Jie; Sabater-Lleal, Maria; Asselbergs, Folkert W; Tregouet, David; Shin, So-Youn; Ding, Jingzhong; Baumert, Jens; Oudot-Mellakh, Tiphaine; Folkersen, Lasse; Johnson, Andrew D; Smith, Nicholas L; Williams, Scott M; et al. (Blood, 2012)
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
Keywords: Adaptor Proteins, Signal Transducing; ARNTL Transcription Factors; ATPases Associated with Diverse Cellular Activities; Cell Line; Cell Line, Tumor; Cohort Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Gene Expression Profiling; Gene Expression Regulation; Gene Frequency; Genome-Wide Association Study; Genotype; Humans; LIM Domain Proteins; Meta-Analysis as Topic; Monocytes; Mucin-3; Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; PPAR gamma; Proteasome Endopeptidase Complex; RNA Interference; Transcription Factors

Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. - Hancock, Dana B; Soler Artigas, Maria; Gharib, Sina A; Henry, Amanda; Manichaikul, Ani; Ramasamy, Adaikalavan; Loth, Daan W; Imboden, Medea; Koch, Beate; McArdle, Wendy L; Smith, Albert V; Smolonska, Joanna; et al. (PLoS Genet, 2012)
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Keywords: Forced Expiratory Volume; Gene Expression; Genome, Human; Genome-Wide Association Study; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Lung; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Smoking; SOX9 Transcription Factor; Vital Capacity

Genome-wide meta-analyses of smoking behaviors in African Americans. - David, S P; Hamidovic, A; Chen, G K; Bergen, A W; Wessel, J; Kasberger, J L; Brown, W M; Petruzella, S; Thacker, E L; Kim, Y; Nalls, M A; Tranah, G J; et al. (Transl Psychiatry, 2012)
The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
Keywords: Adult; African Americans; Aged; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 15; Female; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Nerve Tissue Proteins; Phenotype; Polymorphism, Single Nucleotide; Proteoglycans; Receptors, Nicotinic; Smoking; Statistics as Topic

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. - Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; et al. (Nat Genet, 2012)
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
Keywords: Bone Density; Computational Biology; European Continental Ancestry Group; Extracellular Matrix Proteins; Female; Femur Neck; Fractures, Bone; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Lumbar Vertebrae; Male; Mitochondrial Membrane Transport Proteins; Osteoporosis; Phosphoproteins; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Spectrin

Hemoglobin A1c and arterial and ventricular stiffness in older adults. - Zieman, Susan J; Kamineni, Aruna; Ix, Joachim H; Barzilay, Joshua; Djoussé, Luc; Kizer, Jorge R; Biggs, Mary L; de Boer, Ian H; Chonchol, Michel; Gottdiener, John S; Selvin, Elizabeth; Newman, Anne B; et al. (PLoS One, 2012)
OBJECTIVE: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes. RESEARCH DESIGN & METHODS: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥ 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures. RESULTS: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM. CONCLUSIONS: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.
Keywords: Adult; African Continental Ancestry Group; Aged; Ankle Brachial Index; Arteries; Blood Glucose; Blood Pressure; Body Mass Index; Cross-Sectional Studies; Fasting; Female; Genetic Association Studies; Glycated Hemoglobin A; Glycation End Products, Advanced; Heart Ventricles; Humans; Male; Middle Aged; Ultrasonography; Vascular Stiffness

Impact of blood pressure and blood pressure change during middle age on the remaining lifetime risk for cardiovascular disease: the cardiovascular lifetime risk pooling project. - Allen, Norrina; Berry, Jarett D; Ning, Hongyan; Van Horn, Linda; Dyer, Alan; Lloyd-Jones, Donald M (Circulation, 2012)
BACKGROUND: Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure (BP) at the index age and did not account for changes in BP over time. We examined how changes in BP during middle age affect LTR for CVD, coronary heart disease, and stroke. METHODS AND RESULTS: Data from 7 diverse US cohort studies were pooled. Remaining LTRs for CVD, coronary heart disease, and stroke were estimated for white and black men and women with death free of CVD as a competing event. LTRs for CVD by BP strata and by changes in BP over an average of 14 years were estimated. Starting at 55 years of age, we followed up 61 585 men and women for 700 000 person-years. LTR for CVD was 52.5% (95% confidence interval, 51.3-53.7) for men and 39.9% (95% confidence interval, 38.7-41.0) for women. LTR for CVD was higher for blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22% to 41%, compared with individuals who had or developed hypertension by 55 years of age, 42% to 69%, suggesting a dose-response effect for the length of time at high BP levels. CONCLUSIONS: Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension to reduce the LTR for CVD.
Keywords: Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Female; Follow-Up Studies; Humans; Hypertension; Life Tables; Longitudinal Studies; Male; Middle Aged; Risk Factors

Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study. - Lopez, Oscar L; Becker, James T; Chang, Yue-Fang; Sweet, Robert A; DeKosky, Steven T; Gach, Michael H; Carmichael, Owen T; McDade, Eric; Kuller, Lewis H (Neurology, 2012)
OBJECTIVES AND METHODS: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011. RESULTS: Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years). CONCLUSIONS: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Dementia; Disease Progression; Female; Health Surveys; Humans; Incidence; Male; Risk Factors; Severity of Illness Index

Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study. - Britton, Kathryn A; Mukamal, Kenneth J; Ix, Joachim H; Siscovick, David S; Newman, Anne B; de Boer, Ian H; Thacker, Evan L; Biggs, Mary L; Gaziano, J Michael; Djoussé, Luc (Vasc Med, 2012)
Type 2 diabetes is a risk factor for peripheral artery disease (PAD), and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by two methods. PAD was first defined as the development of an abnormal ankle-brachial index (ABI) (dichotomous outcome) after 6 years of follow-up. PAD was alternatively defined as the development of clinical PAD (time-to-event analysis). The study samples included adults over the age of 65 years who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, body mass index (BMI), smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n = 2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (odds ratio = 1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval [CI] 1.20-2.71). In the clinical PAD analysis (n = 4208), we found a similar relation (hazard ratio = 2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% CI 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.
Keywords: Aged; Ankle Brachial Index; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fasting; Female; Health Surveys; Humans; Incidence; Insulin; Insulin Resistance; Logistic Models; Longitudinal Studies; Male; Odds Ratio; Peripheral Arterial Disease; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; United States

Insulin resistance, cystatin C, and mortality among older adults. - de Boer, Ian H; Katz, Ronit; Chonchol, Michel B; Fried, Linda F; Ix, Joachim H; Kestenbaum, Bryan; Mukamal, Kenneth J; Peralta, Carmen A; Siscovick, David S (Diabetes Care, 2012)
OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes. RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥ 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR). RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models. CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
Keywords: Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Cystatin C; Fasting; Female; Glomerular Filtration Rate; Humans; Insulin Resistance; Life Style; Male; Mortality; Predictive Value of Tests; Proportional Hazards Models; Renal Insufficiency; Risk Factors; Triglycerides; Waist Circumference

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. - Scott, Robert A; Lagou, Vasiliki; Welch, Ryan P; Wheeler, Eleanor; Montasser, May E; Luan, Jian'an; Mägi, Reedik; Strawbridge, Rona J; Rehnberg, Emil; Gustafsson, Stefan; Kanoni, Stavroula; Rasmussen-Torvik, Laura J; et al. (Nat Genet, 2012)
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
Keywords: Adult; Animals; Blood Glucose; Fasting; Female; Gene Frequency; Genome-Wide Association Study; Humans; Insulin; Male; Metabolic Networks and Pathways; Mice; Osmolar Concentration; Quantitative Trait Loci

Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts. - Puhan, Milo A; Hansel, Nadia N; Sobradillo, Patricia; Enright, Paul; Lange, Peter; Hickson, Demarc; Menezes, Ana M; ter Riet, Gerben; Held, Ulrike; Domingo-Salvany, Antonia; Mosenifar, Zab; Antó, Josep M; et al. (BMJ Open, 2012)
BACKGROUND: Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists. OBJECTIVE: To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV(1) to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible. DESIGN: Individual subject data analysis of 10 European and American cohorts (n=13 914). SETTING: Population-based, primary, secondary and tertiary care. PATIENTS: COPD GOLD stages I-IV. MEASUREMENTS: We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses. RESULTS: 1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV(1) 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV(1) alone. INTERPRETATION: The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions.

Lifetime risk and years lived free of total cardiovascular disease. - Wilkins, John T; Ning, Hongyan; Berry, Jarett; Zhao, Lihui; Dyer, Alan R; Lloyd-Jones, Donald M (JAMA, 2012)
CONTEXT: Estimates of lifetime risk for total cardiovascular disease (CVD) may provide projections of the future population burden of CVD and may assist in clinician-patient risk communication. To date, no lifetime risk estimates of total CVD have been reported. OBJECTIVES: To calculate lifetime risk estimates of total CVD by index age (45, 55, 65, 75 years) and risk factor strata and to estimate years lived free of CVD across risk factor strata. DESIGN, SETTING, AND PARTICIPANTS: Pooled survival analysis of as many as 905,115 person-years of data from 1964 through 2008 from 5 National Heart, Lung, and Blood Institute-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study, and Cardiovascular Health Study. All participants were free of CVD at baseline with risk factor data (blood pressure [BP], total cholesterol [TC], diabetes, and smoking status) and total CVD outcome data. MAIN OUTCOME MEASURES: Any total CVD event (including fatal and nonfatal coronary heart disease, all forms of stroke, congestive heart failure, and other CVD deaths). RESULTS: At an index age of 45 years, overall lifetime risk for total CVD was 60.3% (95% CI, 59.3%-61.2%) for men and 55.6% (95% CI, 54.5%-56.7%) for women. Men had higher lifetime risk estimates than women across all index ages. At index ages 55 and 65 years, men and women with at least 1 elevated risk factor (BP, 140-149/90-99 mm Hg; or TC, 200-239 mg/dL; but no diabetes or smoking), 1 major risk factor, or at least 2 major risk factors (BP, ≥160/100 mm Hg or receiving treatment; TC, ≥240 mg/dL or receiving treatment; diabetes mellitus; or current smoking) had lifetime risk estimates to age 95 years that exceeded 50%. Despite an optimal risk factor profile (BP, <120/80 mm Hg; TC, <180 mg/dL; and no smoking or diabetes), men and women at the index age of 55 years had lifetime risks (through 85 years of age) for total CVD of greater than 40% and 30%, respectively. Compared with participants with at least 2 major risk factors, those with an optimal risk factor profile lived up to 14 years longer free of total CVD. CONCLUSIONS: Lifetime risk estimates for total CVD were high (>30%) for all individuals, even those with optimal risk factors in middle age. However, maintenance of optimal risk factor levels in middle age was associated with substantially longer morbidity-free survival.
Keywords: Adult; Aged; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus; Female; Forecasting; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Morbidity; Risk; Risk Factors; Smoking

Lifetime risks of cardiovascular disease. - Berry, Jarett D; Dyer, Alan; Cai, Xuan; Garside, Daniel B; Ning, Hongyan; Thomas, Avis; Greenland, Philip; Van Horn, Linda; Tracy, Russell P; Lloyd-Jones, Donald M (N Engl J Med, 2012)
BACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults. METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event. RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts. CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).
Keywords: Adult; African Americans; Aged; Cardiovascular Diseases; Cohort Effect; European Continental Ancestry Group; Female; Humans; Male; Middle Aged; Risk; Risk Assessment; Risk Factors; United States

Lipid-related markers and cardiovascular disease prediction. - Di Angelantonio, Emanuele; Gao, Pei; Pennells, Lisa; Kaptoge, Stephen; Caslake, Muriel; Thompson, Alexander; Butterworth, Adam S; Sarwar, Nadeem; Wormser, David; Saleheen, Danish; Ballantyne, Christie M; Psaty, Bruce M; et al. (JAMA, 2012)
CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.
Keywords: Aged; Biomarkers; Cardiovascular Diseases; Cholesterol, HDL; Cohort Studies; Female; Humans; Lipoproteins; Male; Middle Aged; Risk Assessment

Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. - Jenny, Nancy S; French, Benjamin; Arnold, Alice M; Strotmeyer, Elsa S; Cushman, Mary; Chaves, Paulo H M; Ding, Jingzhong; Fried, Linda P; Kritchevsky, Stephen B; Rifkin, Dena E; Sarnak, Mark J; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2012)
BACKGROUND: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging. METHODS: We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006. RESULTS: In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality. CONCLUSIONS: Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
Keywords: Aged; Aged, 80 and over; Aging; C-Reactive Protein; Cardiovascular Diseases; Cognition; Cohort Studies; Cross-Sectional Studies; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Longitudinal Studies; Male; Risk Factors; Vermont

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. - Stolk, Lisette; Perry, John R B; Chasman, Daniel I; He, Chunyan; Mangino, Massimo; Sulem, Patrick; Barbalic, Maja; Broer, Linda; Byrne, Enda M; Ernst, Florian; Esko, Tõnu; Franceschini, Nora; et al. (Nat Genet, 2012)
To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
Keywords: Age Factors; DNA Helicases; DNA Polymerase gamma; DNA Primase; DNA Repair; DNA Repair Enzymes; DNA-Directed DNA Polymerase; European Continental Ancestry Group; Exodeoxyribonucleases; Female; Genetic Loci; Genome-Wide Association Study; Humans; Immunity; Menopause; Polymorphism, Single Nucleotide; Proteins

Meta-analysis identifies six new susceptibility loci for atrial fibrillation. - Ellinor, Patrick T; Lunetta, Kathryn L; Albert, Christine M; Glazer, Nicole L; Ritchie, Marylyn D; Smith, Albert V; Arking, Dan E; Müller-Nurasyid, Martina; Krijthe, Bouwe P; Lubitz, Steven A; Bis, Joshua C; Chung, Mina K; et al. (Nat Genet, 2012)
Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Asian Continental Ancestry Group; Atrial Fibrillation; Child; Child, Preschool; European Continental Ancestry Group; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Infant; Infant, Newborn; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Young Adult

Nonesterified fatty acids and risk of sudden cardiac death in older adults. - Djoussé, Luc; Biggs, Mary L; Ix, Joachim H; Kizer, Jorge R; Lemaitre, Rozenn N; Sotoodehnia, Nona; Zieman, Susan J; Mozaffarian, Dariush; Tracy, Russell P; Mukamal, Kenneth J; Siscovick, David S (Circ Arrhythm Electrophysiol, 2012)
BACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death. METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death. CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
Keywords: Aged; Aged, 80 and over; Biomarkers; Death, Sudden, Cardiac; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Humans; Incidence; Male; Proportional Hazards Models; Prospective Studies; Retrospective Studies; Risk Factors

Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. - Butler, Anne M; Yin, Xiaoyan; Evans, Daniel S; Nalls, Michael A; Smith, Erin N; Tanaka, Toshiko; Li, Guo; Buxbaum, Sarah G; Whitsel, Eric A; Alonso, Alvaro; Arking, Dan E; Benjamin, Emelia J; et al. (Circ Cardiovasc Genet, 2012)
BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)). CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
Keywords: Adult; African Americans; Cohort Studies; Electrocardiography; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. - Dastani, Zari; Hivert, Marie-France; Timpson, Nicholas; Perry, John R B; Yuan, Xin; Scott, Robert A; Henneman, Peter; Heid, Iris M; Kizer, Jorge R; Lyytikäinen, Leo-Pekka; Fuchsberger, Christian; Tanaka, Toshiko; et al. (PLoS Genet, 2012)
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Keywords: Adiponectin; African Americans; Asian Continental Ancestry Group; Cholesterol, HDL; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Female; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Metabolic Networks and Pathways; Polymorphism, Single Nucleotide; Waist-Hip Ratio

Persistence and remission of musculoskeletal pain in community-dwelling older adults: results from the cardiovascular health study. - Thielke, Stephen M; Whitson, Heather; Diehr, Paula; O'Hare, Ann; Kearney, Patricia M; Chaudhry, Sarwat I; Zakai, Neil A; Kim, Dae; Sekaran, Nishant; Sale, Joanna E M; Arnold, Alice M; Chaves, Paulo; et al. (J Am Geriatr Soc, 2012)
OBJECTIVES: To characterize longitudinal patterns of musculoskeletal pain in a community sample of older adults over a 6-year period and to identify factors associated with persistence of pain. DESIGN: Secondary analysis of the Cardiovascular Health Study. SETTING: Community-based cohort drawn from four U.S. counties. PARTICIPANTS: Five thousand ninety-three men and women aged 65 and older. MEASUREMENTS: Over a 6-year period, pain was assessed each year using a single question about the presence of pain in any bones or joints during the last year. If affirmative, participants were queried about pain in seven locations (hands, shoulders, neck, back, hips, knees, feet). Participants were categorized according to the percentage of time that pain was present and according to the intermittent or chronic pattern of pain. Factors associated with persistent pain during five remaining years of the study were identified. RESULTS: Over 6 years, 32% of participants reported pain for three or more consecutive years, and 32% reported pain intermittently. Of those who reported pain the first year, 54% were pain free at least once during the follow-up period. Most of the pain at specific body locations was intermittent. Factors associated with remission of pain over 5 years included older age, male sex, better self-rated health, not being obese, taking fewer medications, and having fewer depressive symptoms. Approximately half of those with pain reported fewer pain locations the following year. CONCLUSION: Musculoskeletal pain in older adults, despite high prevalence, is often intermittent. The findings refute the notion that pain is an inevitable, unremitting, or progressive consequence of aging.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Female; Humans; Male; Musculoskeletal Pain; Remission Induction; Residence Characteristics

Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults. - deFilippi, Christopher R; de Lemos, James A; Tkaczuk, Andrew T; Christenson, Robert H; Carnethon, Mercedes R; Siscovick, David S; Gottdiener, John S; Seliger, Stephen L (J Am Coll Cardiol, 2012)
OBJECTIVES: The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults. BACKGROUND: Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified. METHODS: NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25% increment from baseline to ≥190 pg/ml and for cTnT as a >50% increment from baseline in participants with detectable levels (≥3 pg/ml). RESULTS: A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk. CONCLUSIONS: These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.
Keywords: Aged; Biomarkers; Female; Heart Failure; Humans; Male; Motor Activity; Natriuretic Peptide, Brain; Peptide Fragments; Risk Assessment; Troponin

Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults. - Djoussé, Luc; Khawaja, Owais; Bartz, Traci M; Biggs, Mary L; Ix, Joachim H; Zieman, Susan J; Kizer, Jorge R; Tracy, Russell P; Siscovick, David S; Mukamal, Kenneth J (Diabetes Care, 2012)
OBJECTIVE: To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults. RESEARCH DESIGN AND METHODS: We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose ≥ 126 mg/dL, or nonfasting glucose ≥ 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993. RESULTS: Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03). CONCLUSIONS: Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.
Keywords: Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Diabetes Mellitus; Fatty Acid-Binding Proteins; Fatty Acids, Nonesterified; Female; Humans; Male; Prospective Studies

Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). - Khawaja, Owais; Bartz, Traci M; Ix, Joachim H; Heckbert, Susan R; Kizer, Jorge R; Zieman, Susan J; Mukamal, Kenneth J; Tracy, Russell P; Siscovick, David S; Djoussé, Luc (Am J Cardiol, 2012)
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women ≥65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 ± 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.
Keywords: Aged; Atrial Fibrillation; C-Reactive Protein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Lipoproteins, HDL; Lipoproteins, LDL; Male; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Prospective Studies; Sex Factors; Triglycerides; United States

The risk of infection-related hospitalization with decreased kidney function. - Dalrymple, Lorien S; Katz, Ronit; Kestenbaum, Bryan; de Boer, Ian H; Fried, Linda; Sarnak, Mark J; Shlipak, Michael G (Am J Kidney Dis, 2012)
BACKGROUND: Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, estimated by serum cystatin C level, was associated with the risk of infection-related hospitalization in older individuals. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 5,142 Cardiovascular Health Study (CHS) participants with measured serum creatinine and cystatin C and without estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m(2) at enrollment. PREDICTOR: The primary exposure of interest was eGFR using serum cystatin C level (eGFR(SCysC)). OUTCOME: Infection-related hospitalizations during a median follow-up of 11.5 years. RESULTS: In adjusted analyses, eGFR(SCysC) categories of 60-89, 45-59, and 15-44 mL/min/1.73 m(2) were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2). When cause-specific infection was examined, eGFR(SCysC) of 15-44 mL/min/1.73 m(2) was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2). LIMITATIONS: No measures of urinary protein, study limited to principal discharge diagnosis. CONCLUSIONS: Lower kidney function, estimated using cystatin C level, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of decreased kidney function are associated with clinically significant higher risks of serious infection in older individuals.
Keywords: Aged; Cohort Studies; Female; Glomerular Filtration Rate; Hospitalization; Humans; Infection; Kidney; Male; Risk Factors

Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. - de Boer, Ian H; Levin, Gregory; Robinson-Cohen, Cassianne; Biggs, Mary L; Hoofnagle, Andy N; Siscovick, David S; Kestenbaum, Bryan (Ann Intern Med, 2012)
BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration. OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D. DESIGN: Cohort study. SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis. PARTICIPANTS: 1621 white older adults. MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death. RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively. LIMITATION: The observational study was restricted to white participants. CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk. PRIMARY FUNDING SOURCE: National Institutes of Health.
Keywords: Aged; Cause of Death; Female; Follow-Up Studies; Hip Fractures; Humans; Male; Myocardial Infarction; Neoplasms; Proportional Hazards Models; Risk Assessment; Risk Factors; Seasons; United States; Vitamin D; Vitamin D Deficiency

Total and high-molecular-weight adiponectin and risk of incident diabetes in older people. - Kizer, Jorge R; Arnold, Alice M; Benkeser, David; Ix, Joachim H; Djoussé, Luc; Zieman, Susan J; Barzilay, Joshua I; Tracy, Russell P; Mantzoros, Christos S; Siscovick, David S; Mukamal, Kenneth J (Diabetes Care, 2012)
OBJECTIVE: To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults. RESEARCH DESIGN AND METHODS: Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals. RESULTS: Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39-0.63]) and HMW adiponectin (0.42 [0.32-0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables. CONCLUSIONS: In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.
Keywords: Adiponectin; Aged; Diabetes Mellitus; Female; Humans; Male; Risk Factors

Transitions among Health States Using 12 Measures of Successful Aging in Men and Women: Results from the Cardiovascular Health Study. - Thielke, Stephen; Diehr, Paula (J Aging Res, 2012)
Introduction. Successful aging has many dimensions, which may manifest differently in men and women at different ages. Methods. We characterized one-year transitions among health states in 12 measures of successful aging among adults in the Cardiovascular Health Study. The measures included self-rated health, ADLs, IADLs, depression, cognition, timed walk, number of days spent in bed, number of blocks walked, extremity strength, recent hospitalizations, feelings about life as a whole, and life satisfaction. We dichotomized variables into "healthy" or "sick," states, and estimated the prevalence of the healthy state and the probability of transitioning from one state to another, or dying, during yearly intervals. We compared men and women and three age groups (65-74, 75-84, and 85-94). Findings. Measures of successful aging showed similar results by gender. Most participants remained healthy even into advanced ages, although health declined for all measures. Recuperation, although less common with age, still occurred frequently. Men had a higher death rate than women regardless of health status, and were also more likely to remain in the healthy state. Discussion. The results suggest a qualitatively different experience of successful aging between men and women. Men did not simply "age faster" than women.

Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. - Chiang, Charleston W K; Liu, Ching-Ti; Lettre, Guillaume; Lange, Leslie A; Jorgensen, Neal W; Keating, Brendan J; Vedantam, Sailaja; Nock, Nora L; Franceschini, Nora; Reiner, Alex P; Demerath, Ellen W; Boerwinkle, Eric; et al. (Genetics, 2012)
Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.
Keywords: Alleles; Animals; Body Height; Body Mass Index; Child; Conserved Sequence; Dogs; Evolution, Molecular; Female; Genetic Fitness; Genetic Variation; Genome, Human; Genotype; Humans; Inheritance Patterns; Male; Mice; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Rats; Reproduction; Young Adult

Albuminuria is associated with hip fracture risk in older adults: the cardiovascular health study. - Barzilay, J I; Bůžková, P; Chen, Z; de Boer, I H; Carbone, L; Rassouli, N N; Fink, H A; Robbins, J A (Osteoporos Int, 2013)
UNLABELLED: The microcirculation plays an important role in bone health. Here, we examine whether albuminuria, a marker of renal microvascular disease, is associated with the risk of hip fracture in older adults (age, 78 years). We find a small independent association in women but not in men. INTRODUCTION: The microvascular circulation plays an important role in bone physiology. Two studies of middle-aged adults have found that albuminuria (>30 mg albumin/g creatinine), a disorder of the renal microvasculature, is associated with fracture risk. Here, we examine whether albuminuria is related to hip fracture risk and reduced hip bone mineral density (BMD) in older adults with a mean age of 78 years. METHODS: From the Cardiovascular Health Study (41 % male), 3,110 adults with albuminuria testing were followed up for incident hip fracture for up to 9.5 years. BMD was performed in a subset of 1,208 participants. RESULTS: There were 313 hip fractures during follow-up (7.7 % of men; 11.7 % of women). The incidence rate for men, with and without albuminuria, was 1.43 and 0.93/100 person-years of follow-up (p = 0.02); for women, 1.84 and 1.33 (p = 0.04). After adjustment for osteoporosis-related factors, frailty and falling, a doubling of albuminuria was significantly associated with hip fracture risk in women (hazard ratio, 1.12, 95 % CI, 1.001-1.25), but not in men. In the subcohort with BMD measurement, increased urine albumin levels were significantly associated with decreased total hip BMD in men (-0.009 g calcium/cm(2) (-0.017, -0.001); p = 0.04), but not in women. CONCLUSIONS: In older women, albuminuria is associated with a small, but statistically significant, increased risk of hip fracture independent of other explanatory factors. No such risk appears to be present in men, although their total hip BMD is lower in association with albuminuria.
Keywords: Aged; Aged, 80 and over; Albuminuria; Bone Density; Female; Follow-Up Studies; Hip Fractures; Hip Joint; Humans; Incidence; Kaplan-Meier Estimate; Male; Osteoporotic Fractures; Risk Factors; Sex Factors; United States

Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. - Zhang, Lili; Spencer, Kylee L; Voruganti, V Saroja; Jorgensen, Neal W; Fornage, Myriam; Best, Lyle G; Brown-Gentry, Kristin D; Cole, Shelley A; Crawford, Dana C; Deelman, Ewa; Franceschini, Nora; Gaffo, Angelo L; et al. (Am J Epidemiol, 2013)
A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
Keywords: Adult; African Americans; Age Distribution; ATP-Binding Cassette Transporters; Comorbidity; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genetics, Population; Genome-Wide Association Study; Gout; Hormone Replacement Therapy; Humans; Indians, North American; Male; Mexican Americans; Middle Aged; Neoplasm Proteins; Polymorphism, Genetic; Postmenopause; Sex Distribution; United States; Uric Acid

Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. - Yu, Bing; Barbalic, Maja; Brautbar, Ariel; Nambi, Vijay; Hoogeveen, Ron C; Tang, Weihong; Mosley, Thomas H; Rotter, Jerome I; deFilippi, Christopher R; O'Donnell, Christopher J; Kathiresan, Sekar; Rice, Ken; et al. (Circ Cardiovasc Genet, 2013)
BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels. METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004). CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
Keywords: African Continental Ancestry Group; Atherosclerosis; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Nuclear Receptor Coactivator 2; Polymorphism, Single Nucleotide; Prospective Studies; Residence Characteristics; Risk Factors; Troponin T

Association of heat shock proteins with all-cause mortality. - Broer, L; Demerath, E W; Garcia, M E; Homuth, G; Kaplan, R C; Lunetta, K L; Tanaka, T; Tranah, G J; Walter, S; Arnold, A M; Atzmon, G; Harris, T B; et al. (Age (Dordr), 2013)
Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.
Keywords: Aged, 80 and over; Aging; Cause of Death; Forecasting; Genotype; Heat-Shock Proteins; Humans; Longevity; Promoter Regions, Genetic; Retrospective Studies; Transcription, Genetic; United States

Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. - Dewland, Thomas A; Vittinghoff, Eric; Mandyam, Mala C; Heckbert, Susan R; Siscovick, David S; Stein, Phyllis K; Psaty, Bruce M; Sotoodehnia, Nona; Gottdiener, John S; Marcus, Gregory M (Ann Intern Med, 2013)
BACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable. OBJECTIVE: To investigate whether PAC count improves model performance for AF risk. DESIGN: Prospective cohort study. SETTING: 4 U.S. communities. PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990. MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model. RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h. LIMITATION: This study does not establish a causal link between PACs and AF. CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk. PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.
Keywords: Aged; Atrial Fibrillation; Atrial Function; Cause of Death; Electrocardiography; Female; Humans; Male; Models, Statistical; Myocardial Contraction; Prospective Studies; Risk Assessment

Atrial fibrillation and cognitive decline: a longitudinal cohort study. - Thacker, Evan L; McKnight, Barbara; Psaty, Bruce M; Longstreth, W T; Sitlani, Colleen M; Dublin, Sascha; Arnold, Alice M; Fitzpatrick, Annette L; Gottesman, Rebecca F; Heckbert, Susan R (Neurology, 2013)
OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation. METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times. RESULTS: Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95% CI: -5.3, -2.5). CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.
Keywords: Age Factors; Aged; Aged, 80 and over; Atrial Fibrillation; Cognition Disorders; Comorbidity; Female; Humans; Incidence; Longitudinal Studies; Luria-Nebraska Neuropsychological Battery; Male; Predictive Value of Tests

Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. - Grove, Megan L; Yu, Bing; Cochran, Barbara J; Haritunians, Talin; Bis, Joshua C; Taylor, Kent D; Hansen, Mark; Borecki, Ingrid B; Cupples, L Adrienne; Fornage, Myriam; Gudnason, Vilmundur; Harris, Tamara B; et al. (PLoS One, 2013)
Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
Keywords: Aging; Alleles; Cluster Analysis; Cohort Studies; Continental Population Groups; Exome; Female; Gene Frequency; Genomics; Genotype; Heart; Humans; Male; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Sample Size; Self Report; Sequence Analysis, DNA

Cardiomyocyte injury assessed by a highly sensitive troponin assay and sudden cardiac death in the community: the Cardiovascular Health Study. - Hussein, Ayman A; Gottdiener, John S; Bartz, Traci M; Sotoodehnia, Nona; DeFilippi, Christopher; Dickfeld, Timm; Deo, Rajat; Siscovick, David; Stein, Phyllis K; Lloyd-Jones, Donald (J Am Coll Cardiol, 2013)
OBJECTIVES: This study sought to determine the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD). BACKGROUND: The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated. METHODS: Levels of cardiac troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4,431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3,089 subjects. All deaths, including SCD, were adjudicated by a central events committee. RESULTS: Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD (hazard ratio [HR] for +1 log(hsTnT): 2.04, 95% confidence interval [CI]: 1.78 to 2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR: 1.30, 95% CI: 1.05 to 1.62), as well as for incident heart failure and myocardial infarction (HR: 1.26, 95% CI: 1.01 to 1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [fully adjusted HR: 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT ≥12.10 vs. 5.01 to 12.09 vs. ≤ 5.00 pg/ml, respectively; p trend = 0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (fully adjusted HR for +1 pg/ml per year increase from baseline: 1.03, 95% CI: 1.01 to 1.06). CONCLUSIONS: The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.
Keywords: Aged; Ambulatory Care; Biomarkers; Death, Sudden, Cardiac; Female; Heart Arrest; Humans; Longitudinal Studies; Male; Middle Aged; Myocardium; Myocytes, Cardiac; Proportional Hazards Models; Risk Assessment; Troponin T

Circulating 25-hydroxyvitamin D is associated with insulin resistance cross-sectionally but not longitudinally in older adults: The Cardiovascular Health Study. - Danziger, John; Biggs, Mary L; Niemi, Matt; Ix, Joachim H; Kizer, Jorge R; Djoussé, Luc; de Boer, Ian H; Siscovick, David S; Kestenbaum, Bryan; Mukamal, Kenneth J (Metabolism, 2013)
BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear. OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults. METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis. CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.
Keywords: Adiposity; Aged; Anthropometry; Cardiovascular Diseases; Cross-Sectional Studies; Exercise; Female; Humans; Hydroxycholecalciferols; Inflammation; Insulin; Insulin Resistance; Longitudinal Studies; Male; Middle Aged; Obesity; Risk Factors; Surveys and Questionnaires

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative. - den Ruijter, H M; Peters, S A E; Groenewegen, K A; Anderson, T J; Britton, A R; Dekker, J M; Engstrom, G; Eijkemans, M J; Evans, G W; de Graaf, J; Grobbee, D E; Hedblad, B; et al. (Diabetologia, 2013)
AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.
Keywords: Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus; Humans; Myocardial Infarction; Risk Factors; Stroke

Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. - Mukamal, Kenneth J; Wilk, Jemma B; Biggs, Mary L; Jensen, Majken K; Ix, Joachim H; Kizer, Jorge R; Tracy, Russell P; Zieman, Susan J; Mozaffarian, Dariush; Psaty, Bruce M; Siscovick, David S; Djoussé, Luc (Lipids, 2013)
We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.
Keywords: African Americans; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Cohort Studies; European Continental Ancestry Group; Fatty Acid-Binding Proteins; Female; Gene Frequency; Genetic Association Studies; Haplotypes; Humans; Insulin; Linkage Disequilibrium; Male; Polymorphism, Single Nucleotide

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. - van Meurs, Joyce B J; Paré, Guillaume; Schwartz, Stephen M; Hazra, Aditi; Tanaka, Toshiko; Vermeulen, Sita H; Cotlarciuc, Ioana; Yuan, Xin; Mälarstig, Anders; Bandinelli, Stefania; Bis, Joshua C; Blom, Henk; et al. (Am J Clin Nutr, 2013)
BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls. RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.
Keywords: Coronary Artery Disease; Genes; Genetic Loci; Genetic Predisposition to Disease; Genotype; Homocysteine; Humans; Polymorphism, Genetic; Risk Factors

Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants. - Deo, R; Nalls, M A; Avery, C L; Smith, J G; Evans, D S; Keller, M F; Butler, A M; Buxbaum, S G; Li, G; Miguel Quibrera, P; Smith, E N; Tanaka, T; et al. (Heart Rhythm, 2013)
BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans. METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)). RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.
Keywords: Adult; African Americans; Aged; Arrhythmias, Cardiac; Connexin 43; Electrocardiography; Female; Genetic Variation; Genome-Wide Association Study; Genotype; Heart Rate; Humans; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide; Rest; United States

Common variants associated with plasma triglycerides and risk for coronary artery disease. - Do, Ron; Willer, Cristen J; Schmidt, Ellen M; Sengupta, Sebanti; Gao, Chi; Peloso, Gina M; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L; Mora, Samia; et al. (Nat Genet, 2013)
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Keywords: Biological Transport; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Humans; Polymorphism, Single Nucleotide; Risk Factors; Triglycerides

Common variants in Mendelian kidney disease genes and their association with renal function. - Parsa, Afshin; Fuchsberger, Christian; Köttgen, Anna; O'Seaghdha, Conall M; Pattaro, Cristian; de Andrade, Mariza; Chasman, Daniel I; Teumer, Alexander; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; et al. (J Am Soc Nephrol, 2013)
Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
Keywords: Databases, Genetic; European Continental Ancestry Group; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Kidney; Mendelian Randomization Analysis; Phenotype; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic

Decline in health for older adults: five-year change in 13 key measures of standardized health. - Diehr, Paula H; Thielke, Stephen M; Newman, Anne B; Hirsch, Calvin; Tracy, Russell (J Gerontol A Biol Sci Med Sci, 2013)
BACKGROUND: The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others. METHODS: We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest. RESULTS: The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization. CONCLUSIONS: All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions.
Keywords: Activities of Daily Living; Aged; Aging; Cohort Studies; Female; Gait; Health Status; Health Status Indicators; Hospitalization; Humans; Longitudinal Studies; Male; Mental Health; Quality of Life; Self Report; United States

Discovery and refinement of loci associated with lipid levels. - Willer, Cristen J; Schmidt, Ellen M; Sengupta, Sebanti; Peloso, Gina M; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L; Mora, Samia; Beckmann, Jacques S; Bragg-Gresham, Jennifer L; et al. (Nat Genet, 2013)
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
Keywords: African Continental Ancestry Group; Asian Continental Ancestry Group; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Lipids; Triglycerides

Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: the Cardiovascular Health Study. - Locke, Emily; Thielke, Stephen; Diehr, Paula; Wilsdon, Anthony G; Barr, R Graham; Hansel, Nadia; Kapur, Vishesh K; Krishnan, Jerry; Enright, Paul; Heckbert, Susan R; Kronmal, Richard A; Fan, Vincent S (COPD, 2013)
BACKGROUND: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation. METHODS: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &γτ;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years. RESULTS: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years. CONCLUSIONS: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
Keywords: Activities of Daily Living; Aged; Cognition Disorders; Cohort Studies; Comorbidity; Depression; Diabetes Mellitus; Disease Progression; Dyspnea; Female; Heart Failure; Humans; Linear Models; Longitudinal Studies; Male; Muscle Weakness; Myocardial Ischemia; Osteoporosis; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry

Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study. - Djoussé, Luc; Bartz, Traci M; Ix, Joachim H; Kochar, Jinesh; Kizer, Jorge R; Gottdiener, John S; Tracy, Russell P; Mozaffarian, Dariush; Siscovick, David S; Mukamal, Kenneth J; Zieman, Susan J (Eur J Heart Fail, 2013)
AIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure. METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion. CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
Keywords: Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; Fatty Acid-Binding Proteins; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Humans; Male; Proportional Hazards Models; Prospective Studies; Risk Factors; United States; Ventricular Function, Left

Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. - Jensen, Majken K; Bartz, Traci M; Mukamal, Kenneth J; Djoussé, Luc; Kizer, Jorge R; Tracy, Russell P; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Shlipak, Michael; Ix, Joachim H (Diabetes Care, 2013)
OBJECTIVE: Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008. RESULTS: Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88-0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93-1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85-0.97) and 0.87 (0.79-0.95), respectively]. CONCLUSIONS: The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Fetuins; Humans; Incidence; Longitudinal Studies; Male; Risk Factors

Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. - Jovanovich, Anna; Bůzková, Petra; Chonchol, Michel; Robbins, John; Fink, Howard A; de Boer, Ian H; Kestenbaum, Bryan; Katz, Ronit; Carbone, Laura; Lee, Jennifer; Laughlin, Gail A; Mukamal, Kenneth J; et al. (J Clin Endocrinol Metab, 2013)
CONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis. OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults. DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease. PARTICIPANTS: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit. MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants. RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions). CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.
Keywords: Aged; Aged, 80 and over; Bone Density; Female; Fibroblast Growth Factors; Hip Fractures; Humans; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Risk; Spinal Fractures

Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. - Jovanovich, Anna; Ix, Joachim H; Gottdiener, John; McFann, Kim; Katz, Ronit; Kestenbaum, Bryan; de Boer, Ian H; Sarnak, Mark; Shlipak, Michael G; Mukamal, Kenneth J; Siscovick, David; Chonchol, Michel (Atherosclerosis, 2013)
OBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain. METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH. RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]). CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
Keywords: Aged; Female; Fibroblast Growth Factors; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Longitudinal Studies; Male; Renal Insufficiency, Chronic; Risk Factors; Ultrasonography

Fine Mapping and Identification of BMI Loci in African Americans. - Gong, Jian; Schumacher, Fredrick; Lim, Unhee; Hindorff, Lucia A; Haessler, Jeff; Buyske, Steven; Carlson, Christopher S; Rosse, Stephanie; Bůzková, Petra; Fornage, Myriam; Gross, Myron; Pankratz, Nathan; et al. (Am J Hum Genet, 2013)
Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
Keywords: Adult; African Americans; Aged; Aged, 80 and over; Body Mass Index; Female; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Young Adult

Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. - Carlson, Christopher S; Matise, Tara C; North, Kari E; Haiman, Christopher A; Fesinmeyer, Megan D; Buyske, Steven; Schumacher, Fredrick R; Peters, Ulrike; Franceschini, Nora; Ritchie, Marylyn D; Duggan, David J; Spencer, Kylee L; et al. (PLoS Biol, 2013)
The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
Keywords: African Americans; Asian Americans; Body Mass Index; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Hispanic Americans; Humans; Indians, North American; Lipids; Metagenomics; Oceanic Ancestry Group; Polymorphism, Single Nucleotide

Genetic loci for retinal arteriolar microcirculation. - Sim, Xueling; Jensen, Richard A; Ikram, M Kamran; Cotch, Mary Frances; Li, Xiaohui; Macgregor, Stuart; Xie, Jing; Smith, Albert Vernon; Boerwinkle, Eric; Mitchell, Paul; Klein, Ronald; Klein, Barbara E K; et al. (PLoS One, 2013)
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
Keywords: Aged; Aged, 80 and over; Arterioles; Chromosomes, Human, Pair 5; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Male; MEF2 Transcription Factors; Microcirculation; Middle Aged; Models, Genetic; Retinal Vessels

Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. - Fesinmeyer, Megan D; Meigs, James B; North, Kari E; Schumacher, Fredrick R; Bůzková, Petra; Franceschini, Nora; Haessler, Jeffrey; Goodloe, Robert; Spencer, Kylee L; Voruganti, Venkata Saroja; Howard, Barbara V; Jackson, Rebecca; et al. (BMC Med Genet, 2013)
BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
Keywords: Adaptor Proteins, Signal Transducing; Adult; African Americans; Aged; Alleles; Asian Continental Ancestry Group; Blood Glucose; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Female; Gene Frequency; Genetic Loci; Genome-Wide Association Study; Genomics; Hispanic Americans; Humans; Indians, North American; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide; Transcription Factor 7-Like 2 Protein

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. - Jensen, Majken K; Bartz, Traci M; Djoussé, Luc; Kizer, Jorge R; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Psaty, Bruce M; Ix, Joachim H; Mukamal, Kenneth J (Diabetes Care, 2013)
OBJECTIVE: Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. RESULTS: Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS: Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
Keywords: alpha-2-HS-Glycoprotein; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Genotype; Humans; Male; Polymorphism, Single Nucleotide

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. - Reiner, Alexander P; Hartiala, Jaana; Zeller, Tanja; Bis, Joshua C; Dupuis, Josée; Fornage, Myriam; Baumert, Jens; Kleber, Marcus E; Wild, Philipp S; Baldus, Stephan; Bielinski, Suzette J; Fontes, João D; et al. (Hum Mol Genet, 2013)
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
Keywords: Adult; African Americans; Aged; Case-Control Studies; Complement Factor H; Coronary Artery Disease; European Continental Ancestry Group; Female; Gene Expression Regulation, Enzymologic; Genetic Association Studies; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Peroxidase; Polymorphism, Single Nucleotide; Young Adult

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. - Köttgen, Anna; Albrecht, Eva; Teumer, Alexander; Vitart, Veronique; Krumsiek, Jan; Hundertmark, Claudia; Pistis, Giorgio; Ruggiero, Daniela; O'Seaghdha, Conall M; Haller, Toomas; Yang, Qiong; Tanaka, Toshiko; et al. (Nat Genet, 2013)
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Keywords: Analysis of Variance; European Continental Ancestry Group; Gene Frequency; Genetic Loci; Genome-Wide Association Study; Glucose; Gout; Humans; Inhibins; Polymorphism, Single Nucleotide; Signal Transduction; Uric Acid

Genome-wide association of body fat distribution in African ancestry populations suggests new loci. - Liu, Ching-Ti; Monda, Keri L; Taylor, Kira C; Lange, Leslie; Demerath, Ellen W; Palmas, Walter; Wojczynski, Mary K; Ellis, Jaclyn C; Vitolins, Mara Z; Liu, Simin; Papanicolaou, George J; Irvin, Marguerite R; et al. (PLoS Genet, 2013)
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Keywords: Adiposity; African Continental Ancestry Group; Body Fat Distribution; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Obesity; Polymorphism, Single Nucleotide; Waist-Hip Ratio

A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. - Tang, Weihong; Teichert, Martina; Chasman, Daniel I; Heit, John A; Morange, Pierre-Emmanuel; Li, Guo; Pankratz, Nathan; Leebeek, Frank W; Paré, Guillaume; de Andrade, Mariza; Tzourio, Christophe; Psaty, Bruce M; et al. (Genet Epidemiol, 2013)
Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
Keywords: Aged; Aging; Case-Control Studies; Cohort Studies; Female; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide; Regression Analysis; Risk Factors; Venous Thromboembolism

Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu - Wu, Jason H Y; Lemaitre, Rozenn N; Manichaikul, Ani; Guan, Weihua; Tanaka, Toshiko; Foy, Millennia; Kabagambe, Edmond K; Djoussé, Luc; Siscovick, David; Fretts, Amanda M; Johnson, Catherine; King, Irena B; et al. (Circ Cardiovasc Genet, 2013)
BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
Keywords: Adult; Aged; Chromosomes, Human, Pair 2; Cohort Studies; Coronary Disease; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Lipogenesis; Male; Middle Aged; Oleic Acid; Palmitic Acid; Polymorphism, Single Nucleotide; Stearic Acids

Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. - Fox, Ervin R; Musani, Solomon K; Barbalic, Maja; Lin, Honghuang; Yu, Bing; Ogunyankin, Kofo O; Smith, Nicholas L; Kutlar, Abdullah; Glazer, Nicole L; Post, Wendy S; Paltoo, Dina N; Dries, Daniel L; et al. (Circ Cardiovasc Genet, 2013)
BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
Keywords: African Americans; Aged; Cohort Studies; Diastole; Echocardiography; European Continental Ancestry Group; Female; Genome-Wide Association Study; Genotype; Heart; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Systole

A genome-wide association study of depressive symptoms. - Hek, Karin; Demirkan, Ayse; Lahti, Jari; Terracciano, Antonio; Teumer, Alexander; Cornelis, Marilyn C; Amin, Najaf; Bakshis, Erin; Baumert, Jens; Ding, Jingzhong; Liu, Yongmei; Marciante, Kristin; et al. (Biol Psychiatry, 2013)
BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
Keywords: Aged; Aged, 80 and over; Chromosomes, Human, Pair 5; Depression; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

A genome-wide association study of early menopause and the combined impact of identified variants. - Perry, John R B; Corre, Tanguy; Esko, Tõnu; Chasman, Daniel I; Fischer, Krista; Franceschini, Nora; He, Chunyan; Kutalik, Zoltán; Mangino, Massimo; Rose, Lynda M; Vernon Smith, Albert; Stolk, Lisette; et al. (Hum Mol Genet, 2013)
Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
Keywords: Case-Control Studies; Female; Gene Frequency; Genome-Wide Association Study; Humans; Menopause, Premature; Polymorphism, Single Nucleotide; Primary Ovarian Insufficiency; Quantitative Trait Loci; Risk

Genome-wide association study of retinopathy in individuals without diabetes. - Jensen, Richard A; Sim, Xueling; Li, Xiaohui; Cotch, Mary Frances; Ikram, M Kamran; Holliday, Elizabeth G; Eiriksdottir, Gudny; Harris, Tamara B; Jonasson, Fridbert; Klein, Barbara E K; Launer, Lenore J; Smith, Albert Vernon; et al. (PLoS One, 2013)
BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
Keywords: Aged; Aged, 80 and over; Female; Genome-Wide Association Study; Genotype; Histone Deacetylases; Humans; Hypertension; Male; Polymorphism, Single Nucleotide; Repressor Proteins; Retinal Diseases

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. - Berndt, Sonja I; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F; Justice, Anne E; Monda, Keri L; Croteau-Chonka, Damien C; Day, Felix R; Esko, Tõnu; Fall, Tove; et al. (Nat Genet, 2013)
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Keywords: Anthropometry; Body Height; Body Mass Index; Case-Control Studies; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Meta-Analysis as Topic; Obesity; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Waist-Hip Ratio

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. - Tanaka, Toshiko; Ngwa, Julius S; van Rooij, Frank J A; Zillikens, M Carola; Wojczynski, Mary K; Frazier-Wood, Alexis C; Houston, Denise K; Kanoni, Stavroula; Lemaitre, Rozenn N; Luan, Jian'an; Mikkilä, Vera; Renstrom, Frida; et al. (Am J Clin Nutr, 2013)
BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)). CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
Keywords: Alleles; Atherosclerosis; Body Mass Index; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; European Continental Ancestry Group; Fibroblast Growth Factors; Follow-Up Studies; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Life Style; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Quantitative Trait Loci; Surveys and Questionnaires

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. - Hansel, Nadia N; Ruczinski, Ingo; Rafaels, Nicholas; Sin, Don D; Daley, Denise; Malinina, Alla; Huang, Lili; Sandford, Andrew; Murray, Tanda; Kim, Yoonhee; Vergara, Candelaria; Heckbert, Susan R; et al. (Hum Genet, 2013)
Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
Keywords: Adult; Ankyrins; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 14; Cohort Studies; Female; Genome-Wide Association Study; Hepatocyte Nuclear Factor 3-alpha; Humans; Linkage Disequilibrium; Lung; Male; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive

Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. - Hruby, Adela; Ngwa, Julius S; Renstrom, Frida; Wojczynski, Mary K; Ganna, Andrea; Hallmans, Göran; Houston, Denise K; Jacques, Paul F; Kanoni, Stavroula; Lehtimäki, Terho; Lemaitre, Rozenn N; Manichaikul, Ani; et al. (J Nutr, 2013)
Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.
Keywords: Blood Glucose; Female; Genetic Loci; Humans; Insulin; Magnesium; Male; Polymorphism, Single Nucleotide; Trace Elements; TRPM Cation Channels

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. - den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S; Evans, David M; Nolte, Ilja M; Segrè, Ayellet V; Holm, Hilma; Handsaker, Robert E; Westra, Harm-Jan; Johnson, Toby; et al. (Nat Genet, 2013)
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Keywords: Animals; Arrhythmias, Cardiac; Gene Frequency; Genetic Loci; Genome-Wide Association Study; Heart Conduction System; Heart Rate; Humans; Metabolic Networks and Pathways; Polymorphism, Single Nucleotide; Quantitative Trait Loci

Inflammation and sudden cardiac death in a community-based population of older adults: the Cardiovascular Health Study. - Hussein, Ayman A; Gottdiener, John S; Bartz, Traci M; Sotoodehnia, Nona; DeFilippi, Christopher; See, Vincent; Deo, Rajat; Siscovick, David; Stein, Phyllis K; Lloyd-Jones, Donald (Heart Rhythm, 2013)
BACKGROUND: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue. OBJECTIVE: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults. METHODS: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease. RESULTS: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease. CONCLUSION: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Case-Control Studies; Cohort Studies; Death, Sudden, Cardiac; Female; Humans; Inflammation; Interleukin-6; Male; Risk Factors

Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. - Holliday, Elizabeth G; Smith, Albert V; Cornes, Belinda K; Buitendijk, Gabriëlle H S; Jensen, Richard A; Sim, Xueling; Aspelund, Thor; Aung, Tin; Baird, Paul N; Boerwinkle, Eric; Cheng, Ching Yu; van Duijn, Cornelia M; et al. (PLoS One, 2013)
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
Keywords: Apolipoproteins E; Complement Factor H; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Kruppel-Like Transcription Factors; Macular Degeneration; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Proteins; Risk Factors; Zinc Finger Protein Gli3

Insulin resistance and risk of incident heart failure: Cardiovascular Health Study. - Banerjee, Dipanjan; Biggs, Mary L; Mercer, Laina; Mukamal, Kenneth; Kaplan, Robert; Barzilay, Joshua; Kuller, Lewis; Kizer, Jorge R; Djoussé, Luc; Tracy, Russell; Zieman, Susan; Lloyd-Jones, Donald; et al. (Circ Heart Fail, 2013)
BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease. METHODS AND RESULTS: We examined 4425 participants (60% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin). CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.
Keywords: Aged; Female; Heart Atria; Heart Failure; Heart Ventricles; Humans; Incidence; Insulin; Insulin Resistance; Male; Middle Aged; Myocardial Infarction; Organ Size; Proportional Hazards Models; Prospective Studies

Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. - Taylor, Kira C; Carty, Cara L; Dumitrescu, Logan; Bůzková, Petra; Cole, Shelley A; Hindorff, Lucia; Schumacher, Fred R; Wilkens, Lynne R; Shohet, Ralph V; Quibrera, P Miguel; Johnson, Karen C; Henderson, Brian E; et al. (BMC Genet, 2013)
BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study. RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses. CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
Keywords: Female; Genetic Heterogeneity; Genome, Human; Genome-Wide Association Study; Humans; Lipids; Male; Polymorphism, Single Nucleotide; Population Groups

Ischemic stroke is associated with the ABO locus: the EuroCLOT study. - Williams, Frances M K; Carter, Angela M; Hysi, Pirro G; Surdulescu, Gabriela; Hodgkiss, Dylan; Soranzo, Nicole; Traylor, Matthew; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M W; Sudlow, Cathie; Farrall, Martin; et al. (Ann Neurol, 2013)
OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
Keywords: ABO Blood-Group System; Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Brain Ischemia; Cohort Studies; Europe; Female; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Stroke; Young Adult

Kidney function and prevalent and incident frailty. - Dalrymple, Lorien S; Katz, Ronit; Rifkin, Dena E; Siscovick, David; Newman, Anne B; Fried, Linda F; Sarnak, Mark J; Odden, Michelle C; Shlipak, Michael G (Clin J Am Soc Nephrol, 2013)
BACKGROUND AND OBJECTIVES: Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: CHS enrolled community-dwelling adults age ≥65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). Secondary analyses examined eGFR using serum creatinine (eGFR(SCr)). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity. RESULTS: The mean age was 75 years and the median eGFR(cys) was 73 ml/min per 1.73 m(2). Among participants with an eGFR(cys) <45 ml/min per 1.73 m(2), 24% had prevalent frailty. In multivariable analysis and compared with eGFR(cys) ≥90 ml/min per 1.73 m(2), eGFR(cys) categories of 45-59 (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR(cys) categories of 60-75 (incidence rate ratio [IRR], 1.72; 95% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95% CI, 0.90 to 2.60) was not. Lower levels of eGFR(SCr) were not associated with higher risk of prevalent or incident frailty. CONCLUSIONS: In community-dwelling elders, lower eGFR(cys) was associated with a higher risk of prevalent and incident frailty whereas lower eGFR(SCr) was not. These findings highlight the importance of considering non-GFR determinants of kidney function.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Creatinine; Cross-Sectional Studies; Cystatin C; Fatigue; Female; Frail Elderly; Geriatric Assessment; Glomerular Filtration Rate; Humans; Incidence; Independent Living; Kidney; Kidney Diseases; Logistic Models; Male; Motor Activity; Multivariate Analysis; Muscle Weakness; Odds Ratio; Phenotype; Prevalence; Prospective Studies; Risk Factors; Time Factors; United States; Weight Loss

Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study. - Zhang, Lili; Bůzková, Petra; Wassel, Christina L; Roman, Mary J; North, Kari E; Crawford, Dana C; Boston, Jonathan; Brown-Gentry, Kristin D; Cole, Shelley A; Deelman, Ewa; Goodloe, Robert; Wilson, Sarah; et al. (Atherosclerosis, 2013)
BACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque. METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model. RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10(-5)), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05). CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
Keywords: African Americans; Aged; Ankle Brachial Index; Asymptomatic Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Coronary Disease; European Continental Ancestry Group; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Indians, North American; Linear Models; Logistic Models; Male; Mexican Americans; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Predictive Value of Tests; Risk Assessment; Risk Factors; United States

Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. - Huffman, Mark D; Berry, Jarett D; Ning, Hongyan; Dyer, Alan R; Garside, Daniel B; Cai, Xuan; Daviglus, Martha L; Lloyd-Jones, Donald M (J Am Coll Cardiol, 2013)
OBJECTIVES: This study sought to estimate lifetime risk for heart failure (HF) by sex and race. BACKGROUND: Prior estimates of lifetime risk for developing HF range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made. METHODS: Using public-release and internal datasets from National Heart, Lung, and Blood Institute-sponsored cohorts, we estimated lifetime risks for developing HF to age 95 years, with death free of HF as the competing event, among participants in the CHA (Chicago Heart Association Detection Project in Industry), ARIC (Atherosclerosis Risk in Communities), and CHS (Cardiovascular Health Study) cohorts. RESULTS: There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30% to 42% in white men, 20% to 29% in black men, 32% to 39% in white women, and 24% to 46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher blood pressure and body mass index at all ages in both blacks and whites, and did not diminish substantially with advancing index age. CONCLUSIONS: These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.
Keywords: Adolescent; Adult; African Americans; Age Factors; Aged; Anthropometry; Body Mass Index; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Health Surveys; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Prognosis; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; Time Factors; United States; Young Adult

Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies. - Smith, C E; Ngwa, J; Tanaka, T; Qi, Q; Wojczynski, M K; Lemaitre, R N; Anderson, J S; Manichaikul, A; Mikkilä, V; van Rooij, F J A; Ye, Z; Bandinelli, S; et al. (Int J Obes (Lond), 2013)
OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.
Keywords: Adipose Tissue; Adult; African Continental Ancestry Group; Aged; Aged, 80 and over; Body Mass Index; Europe; European Continental Ancestry Group; Fatty Acids; Female; Gene Frequency; Gene-Environment Interaction; Genetic Predisposition to Disease; Genotype; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Male; Middle Aged; Obesity; Phenotype; Polymorphism, Single Nucleotide; Prevalence; United States

Long-term trajectory of two unique cardiac biomarkers and subsequent left ventricular structural pathology and risk of incident heart failure in community-dwelling older adults at low baseline risk. - Glick, Danielle; deFilippi, Christopher R; Christenson, Robert; Gottdiener, John S; Seliger, Stephen L (JACC Heart Fail, 2013)
OBJECTIVES: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death. BACKGROUND: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events. METHODS: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50% and NT-proBNP >25% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality. RESULTS: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8% for cTnT only, 13.2% for NT-proBNP only, and 6.1% for both. After 10 years, cumulative HF incidence was 50.4% versus 12.2% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8% versus 4% for those with increases in both biomarkers versus neither biomarker (p = 0.007). CONCLUSIONS: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death.
Keywords: Aged; Biomarkers; Female; Heart Failure; Heart Ventricles; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Risk Assessment; Time Factors; Troponin T; Ultrasonography

A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. - Monda, Keri L; Chen, Gary K; Taylor, Kira C; Palmer, Cameron; Edwards, Todd L; Lange, Leslie A; Ng, Maggie C Y; Adeyemo, Adebowale A; Allison, Matthew A; Bielak, Lawrence F; Chen, Guanjie; Graff, Mariaelisa; et al. (Nat Genet, 2013)
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
Keywords: African Americans; Body Mass Index; Case-Control Studies; Gene Frequency; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Obesity; Polymorphism, Single Nucleotide

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. - Lambert, J C; Ibrahim-Verbaas, C A; Harold, D; Naj, A C; Sims, R; Bellenguez, C; DeStafano, A L; Bis, J C; Beecham, G W; Grenier-Boley, B; Russo, G; Thorton-Wells, T A; et al. (Nat Genet, 2013)
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Keywords: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cohort Studies; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. - O'Seaghdha, Conall M; Wu, Hongsheng; Yang, Qiong; Kapur, Karen; Guessous, Idris; Zuber, Annie Mercier; Köttgen, Anna; Stoudmann, Candice; Teumer, Alexander; Kutalik, Zoltán; Mangino, Massimo; Dehghan, Abbas; et al. (PLoS Genet, 2013)
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Keywords: Animals; Bone and Bones; Bone Density; Calcium; European Continental Ancestry Group; Gene Expression Regulation; Genome-Wide Association Study; Homeostasis; Humans; Kidney; Mice; Polymorphism, Single Nucleotide

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. - Porcu, Eleonora; Medici, Marco; Pistis, Giorgio; Volpato, Claudia B; Wilson, Scott G; Cappola, Anne R; Bos, Steffan D; Deelen, Joris; den Heijer, Martin; Freathy, Rachel M; Lahti, Jari; Liu, Chunyu; et al. (PLoS Genet, 2013)
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Keywords: Female; Genome-Wide Association Study; Humans; Hyperthyroidism; Hypothyroidism; Male; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Sex Characteristics; Signal Transduction; Thyroid Gland; Thyrotropin; Thyroxine

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. - Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; et al. (Circulation, 2013)
BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
Keywords: Adolescent; Adult; African Continental Ancestry Group; Aged; Aged, 80 and over; Cardiovascular Diseases; Coronary Artery Disease; European Continental Ancestry Group; Female; Fibrinogen; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Hispanic Americans; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Risk Factors; Stroke; Venous Thromboembolism; Young Adult

No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. - Dumitrescu, Logan; Carty, Cara L; Franceschini, Nora; Hindorff, Lucia A; Cole, Shelley A; Bůzková, Petra; Schumacher, Fredrick R; Eaton, Charles B; Goodloe, Robert J; Duggan, David J; Haessler, Jeff; Cochran, Barbara; et al. (Hum Genet, 2013)
Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
Keywords: Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Ethnic Groups; Female; Gene Frequency; Gene-Environment Interaction; Genetics, Population; Genome-Wide Association Study; Humans; Lipid Metabolism; Male; Polymorphism, Single Nucleotide; Prevalence; Smoking; Triglycerides; Young Adult

Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults. - Djoussé, Luc; Maziarz, Marlena; Biggs, Mary L; Ix, Joachim H; Zieman, Susan J; Kizer, Jorge R; Lemaitre, Rozenn N; Mozaffarian, Dariush; Tracy, Russell P; Mukamal, Kenneth J; Siscovick, David S; Sotoodehnia, Nona (Cardiol Res Pract, 2013)
Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study. - Djoussé, Luc; Benkeser, David; Arnold, Alice; Kizer, Jorge R; Zieman, Susan J; Lemaitre, Rozenn N; Tracy, Russell P; Gottdiener, John S; Mozaffarian, Dariush; Siscovick, David S; Mukamal, Kenneth J; Ix, Joachim H (Circ Heart Fail, 2013)
BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF). METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6%-19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09-1.23]). CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.
Keywords: Aged; Aged, 80 and over; Biomarkers; Comorbidity; Fatty Acids, Nonesterified; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Linear Models; Male; Multivariate Analysis; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors; United States

Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. - Dumitrescu, Logan; Carty, Cara L; Franceschini, Nora; Hindorff, Lucia A; Cole, Shelley A; Bůzková, Petra; Schumacher, Fredrick R; Eaton, Charles B; Goodloe, Robert J; Duggan, David J; Haessler, Jeff; Cochran, Barbara; et al. (Ann Hum Genet, 2013)
Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
Keywords: Adult; Aged; European Continental Ancestry Group; Female; Genetic Association Studies; Genome-Wide Association Study; Humans; Lipids; Male; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Risk Factors

Prediction and classification of cardiovascular disease risk in older adults with diabetes. - Mukamal, K J; Kizer, J R; Djoussé, L; Ix, J H; Zieman, S; Siscovick, D S; Sibley, C T; Tracy, R P; Arnold, A M (Diabetologia, 2013)
AIMS/HYPOTHESIS: We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis. METHODS: As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred. RESULTS: The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle-brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima-media thickness modestly improved discrimination (C statistic 0.68; p = 0.002) and classification (net reclassification improvement [NRI] 0.12; p = 0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures. CONCLUSIONS/INTERPRETATION: Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Blood Pressure; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cholesterol, HDL; Diabetes Mellitus; Female; Humans; Male; Myocardial Infarction; Regression Analysis; Risk Factors; Stroke

The QT interval and risk of incident atrial fibrillation. - Mandyam, Mala C; Soliman, Elsayed Z; Alonso, Alvaro; Dewland, Thomas A; Heckbert, Susan R; Vittinghoff, Eric; Cummings, Steven R; Ellinor, Patrick T; Chaitman, Bernard R; Stocke, Karen; Applegate, William B; Arking, Dan E; et al. (Heart Rhythm, 2013)
BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas. RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts. CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.
Keywords: Aged; Atrial Fibrillation; Cohort Studies; Electrocardiography; Female; Humans; Incidence; Long QT Syndrome; Male; Middle Aged; Risk Factors

Racial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study. - Jensen, Paul N; Thacker, Evan L; Dublin, Sascha; Psaty, Bruce M; Heckbert, Susan R (J Am Geriatr Soc, 2013)
This study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95% CI = 1.18-1.43). Overall, the relative risk of AF was 25% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95% CI = 0.64-0.87) and 45% lower after adjustment for all considered risk factors (HR = 0.55, 95% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.
Keywords: Aged; Atrial Fibrillation; Continental Population Groups; Female; Follow-Up Studies; Humans; Incidence; Male; Prevalence; Risk Assessment; Risk Factors; Stroke; United States

Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study). - van Ballegooijen, Adriana J; Visser, Marjolein; Kestenbaum, Bryan; Siscovick, David S; de Boer, Ian H; Gottdiener, John S; deFilippi, Christopher R; Brouwer, Ingeborg A (Am J Cardiol, 2013)
Vitamin D and parathyroid hormone (PTH) may affect cardiovascular health in patients with kidney disease and in the general population. The aim of this study was to investigate associations of serum 25-hydroxyvitamin D (25(OH)D) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic, and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25(OH)D and intact PTH concentrations were measured using mass spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide, cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9 ± 4.9 years, 69.7% were women, and 21% had chronic kidney disease (glomerular filtration rate <60 ml/min). Mean 25(OH)D was 25.2 ± 10.2 ng/ml, and median PTH was 51 pg/ml (range 39 to 65). After adjustment, 25(OH)D was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels ≥65 pg/ml were associated with greater N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass in patients with chronic kidney disease. The regression coefficients were: 120 pg/ml (95% confidence interval 36.1 to 204), 5.2 pg/ml (95% confidence interval 3.0 to 7.4), and 17 g (95% confidence interval 6.2 to 27.8) (p <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. In conclusion, in older adults with chronic kidney disease, PTH excess is associated with higher N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass. These findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.
Keywords: Adult; Aged; Biomarkers; Cardiovascular Diseases; Echocardiography; Electrocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Incidence; Male; Mass Spectrometry; Middle Aged; Parathyroid Hormone; Prospective Studies; United States; Vitamin D

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. - Simone, Benedetto; De Stefano, Valerio; Leoncini, Emanuele; Zacho, Jeppe; Martinelli, Ida; Emmerich, Joseph; Rossi, Elena; Folsom, Aaron R; Almawi, Wassim Y; Scarabin, Pierre Y; den Heijer, Martin; Cushman, Mary; et al. (Eur J Epidemiol, 2013)
Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.
Keywords: Case-Control Studies; Factor V; Genetic Predisposition to Disease; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Prothrombin; Risk Factors; Venous Thromboembolism

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. - Randall, Joshua C; Winkler, Thomas W; Kutalik, Zoltán; Berndt, Sonja I; Jackson, Anne U; Monda, Keri L; Kilpeläinen, Tuomas O; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F; et al. (PLoS Genet, 2013)
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Keywords: Anthropometry; Body Height; Body Mass Index; Body Weight; Body Weights and Measures; Female; Genetic Loci; Genome, Human; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Sex Characteristics; Waist Circumference; Waist-Hip Ratio

Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults. - Kizer, Jorge R; Benkeser, David; Arnold, Alice M; Djoussé, Luc; Zieman, Susan J; Mukamal, Kenneth J; Tracy, Russell P; Mantzoros, Christos S; Siscovick, David S; Gottdiener, John S; Ix, Joachim H (J Clin Endocrinol Metab, 2013)
CONTEXT: Adiponectin is atheroprotective in the laboratory, but prospective studies have shown opposite associations with cardiovascular disease (CVD) in healthy middle-aged populations (protective) and older cohorts (adverse). Whether this relates to different proportions of high-molecular-weight (HMW) adiponectin is unknown. OBJECTIVE: The aim of the study was to test the hypothesis that total adiponectin is directly associated, but HMW adiponectin is inversely related, with CVD in older adults. DESIGN, SETTING, AND PARTICIPANTS: We evaluated 3290 participants free of prevalent CVD in a longitudinal cohort study of U.S. adults aged 65 yr and older. MAIN OUTCOME MEASURES: We measured incident CVD (n = 1291), comprising coronary heart disease and ischemic stroke. RESULTS: Total and HMW adiponectin were tightly correlated (r = 0.94). Cubic splines adjusted for potential confounders revealed that the associations of total and HMW adiponectin with CVD were U-shaped, with inflection points of 20 and 10 mg/liter, respectively. After controlling for potential confounding, levels of total and HMW adiponectin below these cutpoints tended to be inversely associated with incident CVD, driven by their significant or near-significant relations with coronary heart disease [hazard ratio (HR), 0.85 per sd increase; 95% confidence interval (CI), 0.75-96; and HR, 0.87; 95% CI, 0.75-1.01, respectively]. These associations were abrogated by additional inclusion of putative metabolic intermediates. Above these cutpoints, however, both total and HMW adiponectin were significantly directly associated with CVD after adjustment for confounders and, particularly, mediators (HR, 1.20 per sd increase; 95% CI, 1.06-1.35; and HR, 1.12; 95% CI, 1.02-1.24, respectively). CONCLUSION: In community-living elders, total and HMW adiponectin showed similar U-shaped relationships with CVD. The inverse relation in the lower range, but not the direct association at the higher end, disappeared after inclusion of putative intermediates, suggesting that high levels may reflect adverse processes separate from adiponectin's beneficial glycometabolic properties.
Keywords: Adiponectin; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Humans; Male; Molecular Weight; Residence Characteristics; Risk Factors; Stroke

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. - Wu, Ying; Waite, Lindsay L; Jackson, Anne U; Sheu, Wayne H-H; Buyske, Steven; Absher, Devin; Arnett, Donna K; Boerwinkle, Eric; Bonnycastle, Lori L; Carty, Cara L; Cheng, Iona; Cochran, Barbara; et al. (PLoS Genet, 2013)
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Keywords: African Americans; Apolipoproteins A; Cholesterol, HDL; Cholesterol, LDL; European Continental Ancestry Group; Genome-Wide Association Study; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Proprotein Convertases; Serine Endopeptidases; Triglycerides

Use of antihypertensive medications and breast cancer risk. - Saltzman, Babette S; Weiss, Noel S; Sieh, Weiva; Fitzpatrick, Annette L; McTiernan, Anne; Daling, Janet R; Li, Christopher I (Cancer Causes Control, 2013)
PURPOSE: Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent. METHODS: We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ≥65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression. RESULTS: Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk. CONCLUSIONS: While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.
Keywords: Aged; Aged, 80 and over; Antihypertensive Agents; Breast Neoplasms; Cohort Studies; Female; Humans; Proportional Hazards Models; Prospective Studies; Risk Factors; United States

ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. - London, Stephanie J; Gao, Wei; Gharib, Sina A; Hancock, Dana B; Wilk, Jemma B; House, John S; Gibbs, Richard A; Muzny, Donna M; Lumley, Thomas; Franceschini, Nora; North, Kari E; Psaty, Bruce M; et al. (Circ Cardiovasc Genet, 2014)
BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4. METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region. CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
Keywords: ADAM Proteins; Aged; Aged, 80 and over; Aging; Cohort Studies; Female; Genetic Variation; Genome-Wide Association Study; Genomics; Heart Diseases; Humans; Lung; Male; Middle Aged; Polymorphism, Single Nucleotide; Sequence Analysis, DNA

Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults. - Kizer, Jorge R; Benkeser, David; Arnold, Alice M; Ix, Joachim H; Mukamal, Kenneth J; Djoussé, Luc; Tracy, Russell P; Siscovick, David S; Psaty, Bruce M; Zieman, Susan J (Atherosclerosis, 2014)
BACKGROUND: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined. METHODS: To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older. RESULTS: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke. CONCLUSIONS: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.
Keywords: Aged; Albumins; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Coronary Disease; Creatinine; Female; Glomerular Filtration Rate; Glycation End Products, Advanced; Humans; Immunoassay; Incidence; Lysine; Male; Oxidative Stress; Proportional Hazards Models; Stroke; Treatment Outcome

Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. - Gore, M Odette; Seliger, Stephen L; deFilippi, Christopher R; Nambi, Vijay; Christenson, Robert H; Hashim, Ibrahim A; Hoogeveen, Ron C; Ayers, Colby R; Sun, Wensheng; McGuire, Darren K; Ballantyne, Christie M; de Lemos, James A (J Am Coll Cardiol, 2014)
OBJECTIVES: The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts. BACKGROUND: The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization. METHODS: Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race. RESULTS: The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold. CONCLUSIONS: Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.
Keywords: Adult; Age Factors; Aged; Biological Assay; Biomarkers; Blood Chemical Analysis; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Myocardial Infarction; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors; Troponin T

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. - Holmes, Michael V; Dale, Caroline E; Zuccolo, Luisa; Silverwood, Richard J; Guo, Yiran; Ye, Zheng; Prieto-Merino, David; Dehghan, Abbas; Trompet, Stella; Wong, Andrew; Cavadino, Alana; Drogan, Dagmar; et al. (BMJ, 2014)
OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
Keywords: Adult; Aged; Alcohol Dehydrogenase; Alcohol Drinking; Biomarkers; Coronary Disease; Female; Genetic Markers; Genotype; Humans; Male; Mendelian Randomization Analysis; Middle Aged; Models, Statistical; Polymorphism, Single Nucleotide; Stroke

Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis. - Ageno, Walter; Di Minno, Matteo N D; Ay, Cihan; Jang, Moon Ju; Hansen, John-Bjarne; Steffen, Lyn M; Vaya, Amparo; Rattazzi, Marcello; Pabinger, Ingrid; Oh, Doyeun; Di Minno, Giovanni; Braekkan, Sigrid K; et al. (Arterioscler Thromb Vasc Biol, 2014)
OBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation. APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE. CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.
Keywords: Adult; Aged; Case-Control Studies; Cohort Studies; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Risk Factors; Venous Thromboembolism

Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. - Cornes, Belinda K; Brody, Jennifer A; Nikpoor, Naghmeh; Morrison, Alanna C; Chu, Huan; Ahn, Byung Soo; Wang, Shuai; Dauriz, Marco; Barzilay, Joshua I; Dupuis, Josée; Florez, Jose C; Coresh, Josef; et al. (Circ Cardiovasc Genet, 2014)
BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
Keywords: Aged; Aged, 80 and over; Aging; Blood Glucose; Chromosomes, Human, Pair 11; Cohort Studies; Death Domain Receptor Signaling Adaptor Proteins; Diabetes Mellitus, Type 2; Fasting; Female; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Genomics; Guanine Nucleotide Exchange Factors; Heart Diseases; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide; Sequence Analysis, DNA

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. - Peloso, Gina M; Auer, Paul L; Bis, Joshua C; Voorman, Arend; Morrison, Alanna C; Stitziel, Nathan O; Brody, Jennifer A; Khetarpal, Sumeet A; Crosby, Jacy R; Fornage, Myriam; Isaacs, Aaron; Jakobsdottir, Johanna; et al. (Am J Hum Genet, 2014)
Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; African Continental Ancestry Group; Aged; Alleles; Animals; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Coronary Disease; European Continental Ancestry Group; Female; Gene Frequency; Genetic Association Studies; Genetic Code; Genetic Variation; Humans; Linear Models; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Middle Aged; Phenotype; Sequence Analysis, DNA; Subtilisins; Triglycerides

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. - Bis, Joshua C; DeStefano, Anita; Liu, Xiaoming; Brody, Jennifer A; Choi, Seung Hoan; Verhaaren, Benjamin F J; Debette, Stephanie; Ikram, M Arfan; Shahar, Eyal; Butler, Kenneth R; Gottesman, Rebecca F; Muzny, Donna; et al. (PLoS One, 2014)
BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
Keywords: Cell Adhesion Molecules, Neuronal; European Continental Ancestry Group; Female; Genetic Association Studies; Genetic Heterogeneity; Humans; Introns; Ischemia; Male; Myocardial Infarction; Polymorphism, Single Nucleotide; Prospective Studies; Sequence Analysis, DNA

Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study. - Longstreth, W T; Diehr, Paula H; Yee, Laura M; Newman, Anne B; Beauchamp, Norman J (J Am Geriatr Soc, 2014)
OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes. DESIGN: Longitudinal cohort study. SETTING: Cardiovascular Health Study. PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses. MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses. RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38%) and not able (38%). CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.
Keywords: Activities of Daily Living; Aged; Atrophy; Brain; Brain Infarction; Cohort Studies; Disability Evaluation; Female; Health Status; Humans; Leukoaraiosis; Longevity; Longitudinal Studies; Magnetic Resonance Imaging; Male; Prognosis; Regression Analysis; United States

The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels. - van Leeuwen, Elisabeth M; Smouter, Françoise A S; Kam-Thong, Tony; Karbalai, Nazanin; Smith, Albert V; Harris, Tamara B; Launer, Lenore J; Sitlani, Colleen M; Li, Guo; Brody, Jennifer A; Bis, Joshua C; White, Charles C; et al. (PLoS One, 2014)
Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.
Keywords: Cholesterol, HDL; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS). - Rosenberg, Michael A; Maziarz, Marlena; Tan, Alex Y; Glazer, Nicole L; Zieman, Susan J; Kizer, Jorge R; Ix, Joachim H; Djoussé, Luc; Siscovick, David S; Heckbert, Susan R; Mukamal, Kenneth J (Am Heart J, 2014)
BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.
Keywords: Aged; Atrial Fibrillation; Biomarkers; Cardiomyopathies; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Female; Fibrosis; Follow-Up Studies; Humans; Incidence; Male; Peptide Fragments; Procollagen; Prospective Studies; Risk Factors; Time Factors; Transforming Growth Factor beta1; United States

Circulating levels of carboxy‐methyl‐lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study. - Barzilay, Joshua I; Bůzková, Petra; Zieman, Susan J; Kizer, Jorge R; Djoussé, Luc; Ix, Joachim H; Tracy, Russell P; Siscovick, David S; Cauley, Jane A; Mukamal, Kenneth J (J Bone Miner Res, 2014)
Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.
Keywords: Age Factors; Aged; Female; Follow-Up Studies; Glycation End Products, Advanced; Hip Fractures; Humans; Incidence; Lysine; Male; Prospective Studies; Retrospective Studies; Risk Factors

Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration. - Bots, Michiel L; Groenewegen, Karlijn A; Anderson, Todd J; Britton, Annie R; Dekker, Jacqueline M; Engström, Gunnar; Evans, Greg W; de Graaf, Jacqueline; Grobbee, Diederick E; Hedblad, Bo; Hofman, Albert; Holewijn, Suzanne; et al. (Hypertension, 2014)
Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
Keywords: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Cohort Studies; Female; Humans; Hypertension; Male; Meta-Analysis as Topic; Middle Aged; Risk Assessment; Risk Factors

A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. - Ilkhanoff, Leonard; Arking, Dan E; Lemaitre, Rozenn N; Alonso, Alvaro; Chen, Lin Y; Durda, Peter; Hesselson, Stephanie E; Kerr, Kathleen F; Magnani, Jared W; Marcus, Gregory M; Schnabel, Renate B; Smith, J Gustav; et al. (J Cardiovasc Electrophysiol, 2014)
OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans. BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored. METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS). RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29). CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.
Keywords: Adult; African Americans; Aged; Aged, 80 and over; Atrial Fibrillation; Case-Control Studies; Cohort Studies; Death, Sudden, Cardiac; Female; Genetic Variation; Humans; Male; Middle Aged; NAV1.5 Voltage-Gated Sodium Channel; Prospective Studies; Risk Factors; Single-Blind Method

Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. - Coresh, Josef; Turin, Tanvir Chowdhury; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Appel, Lawrence J; Arima, Hisatomi; Chadban, Steven J; Cirillo, Massimo; Djurdjev, Ognjenka; Green, Jamie A; Heine, Gunnar H; et al. (JAMA, 2014)
IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
Keywords: Adult; Aged; Aged, 80 and over; Cohort Studies; Creatinine; Disease Progression; Endpoint Determination; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Reference Values; Risk

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events. - Fowkes, F G R; Murray, G D; Butcher, I; Folsom, A R; Hirsch, A T; Couper, D J; deBacker, G; Kornitzer, M; Newman, A B; Sutton-Tyrrell, K C; Cushman, M; Lee, A J; et al. (Eur J Prev Cardiol, 2014)
BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.
Keywords: Adult; Aged; Aged, 80 and over; Ankle Brachial Index; Cardiovascular Diseases; Europe; European Continental Ancestry Group; Female; Humans; Male; Middle Aged; Models, Statistical; Predictive Value of Tests; Prognosis; Reproducibility of Results; Risk Assessment; Risk Factors; Sex Factors; Time Factors; United States; Young Adult

Disability and recovery of independent function in obstructive lung disease: the cardiovascular health study. - Fan, Vincent S; Locke, Emily R; Diehr, Paula; Wilsdon, Anthony; Enright, Paul; Yende, Sachin; Avdalovic, Mark; Barr, Graham; Kapur, Vishesh K; Thomas, Rachel; Krishnan, Jerry A; Lovasi, Gina; et al. (Respiration, 2014)
BACKGROUND: Chronic obstructive lung disease frequently leads to disability. Older patients may experience transitions between states of disability and independence over time. OBJECTIVE: To identify factors associated with transition between states of disability and independent function in obstructive lung disease. METHODS: We analyzed data on 4,394 participants in the Cardiovascular Health Study who completed prebronchodilator spirometry. We calculated the 1-year probability of developing and resolving impairment in ≥1 instrumental activity of daily living (IADL) or ≥1 activity of daily living (ADL) using transition probability analysis. We identified factors associated with resolving disability using relative risk (RR) regression. RESULTS: The prevalence of IADL impairment was higher with moderate (23.9%) and severe (36.9%) airflow obstruction compared to normal spirometry (22.5%; p < 0.001). Among participants with severe airflow obstruction, 23.5% recovered independence in IADLs and 40.5% recovered independence in ADLs. In the adjusted analyses, airflow obstruction predicted the development of IADL, but not ADL impairment. Participants with severe airflow obstruction were less likely to resolve IADL impairment [RR 0.67 and 95% confidence interval (CI) 0.49-0.94]. Compared to the most active individuals (i.e. who walked ≥28 blocks per week), walking less was associated with a decreased likelihood of resolving IADL impairment (7-27 blocks: RR 0.81 and 95% CI 0.69-0.86 and <7 blocks: RR 0.73 and 95% CI 0.61-0.86). Increased strength (RR 1.16 and 95% CI 1.05-1.29) was associated with resolving IADL impairment. CONCLUSIONS: Disability is common in older people, especially in those with severe airflow obstruction. Increased physical activity and muscle strength are associated with recovery. Research is needed on interventions to improve these factors among patients with obstructive lung disease and disability.
Keywords: Activities of Daily Living; Aged; Cardiac Rehabilitation; Cardiovascular Diseases; Disability Evaluation; Exercise Test; Female; Humans; Independent Living; Longitudinal Studies; Male; Motor Activity; Muscle Strength; Outcome Assessment (Health Care); Pulmonary Disease, Chronic Obstructive; Recovery of Function; Risk Assessment; Severity of Illness Index; Spirometry; United States

Do changes in circulating biomarkers track with each other and with functional changes in older adults? - Sanders, Jason L; Ding, Victoria; Arnold, Alice M; Kaplan, Robert C; Cappola, Anne R; Kizer, Jorge R; Boudreau, Robert M; Cushman, Mary; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2014)
BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults. METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes. RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04). CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.
Keywords: Adiponectin; Aged; Aged, 80 and over; Aging; Biomarkers; Cholesterol; Cognition; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Gait; Hand Strength; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-6; Male; Neuropsychological Tests; Psychomotor Performance; Time Factors

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. - Avery, C L; Sitlani, C M; Arking, D E; Arnett, D K; Bis, J C; Boerwinkle, E; Buckley, B M; Ida Chen, Y-D; de Craen, A J M; Eijgelsheim, M; Enquobahrie, D; Evans, D S; et al. (Pharmacogenomics J, 2014)
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
Keywords: Computer Simulation; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; European Continental Ancestry Group; Gene-Environment Interaction; Genome-Wide Association Study; Humans; Linear Models; Long QT Syndrome; Markov Chains; Pharmacogenetics; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable

Effect of dementia on the use of drugs for secondary prevention of ischemic heart disease. - Fowler, Nicole R; Barnato, Amber E; Degenholtz, Howard B; Curcio, Angela M; Becker, James T; Kuller, Lewis H; Lopez, Oscar L (J Aging Res, 2014)
Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36-0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.

Effect of genetic variants associated with plasma homocysteine levels on stroke risk. - Cotlarciuc, Ioana; Malik, Rainer; Holliday, Elizabeth G; Ahmadi, Kourosh R; Paré, Guillaume; Psaty, Bruce M; Fornage, Myriam; Hasan, Nazeeha; Rinne, Paul E; Ikram, M Arfan; Markus, Hugh S; Rosand, Jonathan; et al. (Stroke, 2014)
BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.
Keywords: Brain Ischemia; Cohort Studies; Europe; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome; Homocysteine; Humans; Polymorphism, Single Nucleotide; Risk; Stroke

Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. - Ganesh, Santhi K; Chasman, Daniel I; Larson, Martin G; Guo, Xiuqing; Verwoert, Germain; Bis, Joshua C; Gu, Xiangjun; Smith, Albert V; Yang, Min-Lee; Zhang, Yan; Ehret, Georg; Rose, Lynda M; et al. (Am J Hum Genet, 2014)
Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.
Keywords: Blood Pressure; Genome-Wide Association Study; Humans; Longitudinal Studies; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci

Enhancing case ascertainment of Parkinson's disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study. - Ton, Thanh G N; Biggs, Mary Lou; Comer, Diane; Curtis, Lesley; Hu, Shu-Ching; Thacker, Evan L; Searles Nielsen, Susan; Delaney, Joseph A; Landsittel, Douglas; Longstreth, William T; Checkoway, Harvey; Jain, Samay (Pharmacoepidemiol Drug Saf, 2014)
PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson's disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics. METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education. RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm. CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.
Keywords: Aged; Aged, 80 and over; Algorithms; Antiparkinson Agents; Cohort Studies; Databases, Factual; Female; Hospitalization; Humans; Incidence; Logistic Models; Male; Medicare; Parkinson Disease; Prevalence; Prospective Studies; Smoking; Time Factors; United States

Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. - de Boer, Ian H; Sachs, Michael C; Chonchol, Michel; Himmelfarb, Jonathan; Hoofnagle, Andrew N; Ix, Joachim H; Kremsdorf, Robin A; Lin, Yvonne S; Mehrotra, Rajnish; Robinson-Cohen, Cassianne; Siscovick, David S; Steffes, Michael W; et al. (Am J Kidney Dis, 2014)
BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712). PREDICTOR: eGFR. OUTCOME: Circulating 24,25(OH)2D3 concentration. MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry. RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3. LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism. CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.
Keywords: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Observational Studies as Topic; Randomized Controlled Trials as Topic; Young Adult

Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. - Seyerle, Amanda A; Young, Alicia M; Jeff, Janina M; Melton, Phillip E; Jorgensen, Neal W; Lin, Yi; Carty, Cara L; Deelman, Ewa; Heckbert, Susan R; Hindorff, Lucia A; Jackson, Rebecca D; Martin, Lisa W; et al. (Epidemiology, 2014)
BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
Keywords: Aged; Continental Population Groups; Electrocardiography; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Long QT Syndrome; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Risk Factors

Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study. - Garimella, Pranav S; Ix, Joachim H; Katz, Ronit; Chonchol, Michel B; Kestenbaum, Bryan R; de Boer, Ian H; Siscovick, David S; Shastri, Shani; Hiramoto, Jade S; Shlipak, Michael G; Sarnak, Mark J (Atherosclerosis, 2014)
BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known. METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively. RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70). CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.
Keywords: Aged; Ankle Brachial Index; Cardiovascular Diseases; Cross-Sectional Studies; Fibroblast Growth Factors; Humans; Incidence; Peripheral Arterial Disease; Risk Factors

Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). - Mathew, Jehu S; Sachs, Michael C; Katz, Ronit; Patton, Kristen K; Heckbert, Susan R; Hoofnagle, Andrew N; Alonso, Alvaro; Chonchol, Michel; Deo, Rajat; Ix, Joachim H; Siscovick, David S; Kestenbaum, Bryan; et al. (Circulation, 2014)
BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction. METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23. CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
Keywords: Aged; Aged, 80 and over; Atrial Fibrillation; Comorbidity; Ethnic Groups; Female; Fibroblast Growth Factor 3; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Phosphates; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; United States; Ventricular Dysfunction, Left; Ventricular Remodeling; Vitamin D