@article {817, title = {Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study.}, journal = {Am J Hum Genet}, volume = {76}, year = {2005}, month = {2005 Mar}, pages = {463-77}, abstract = {

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.

}, keywords = {African Americans, Aged, Aging, Algorithms, Cardiovascular Diseases, Cohort Studies, Female, Genetics, Population, Genotype, Humans, Male, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Socioeconomic Factors}, issn = {0002-9297}, doi = {10.1086/428654}, author = {Reiner, Alexander P and Ziv, Elad and Lind, Denise L and Nievergelt, Caroline M and Schork, Nicholas J and Cummings, Steven R and Phong, Angie and Burchard, Esteban Gonz{\'a}lez and Harris, Tamara B and Psaty, Bruce M and Kwok, Pui-Yan} } @article {927, title = {African ancestry, socioeconomic status, and kidney function in elderly African Americans: a genetic admixture analysis.}, journal = {J Am Soc Nephrol}, volume = {17}, year = {2006}, month = {2006 Dec}, pages = {3491-6}, abstract = {

Kidney disease is a major public health problem in the United States that affects African Americans disproportionately. The relative contribution of environmental and genetic factors to the increased burden of kidney disease among African Americans is unknown. The associations of genetic African ancestry and socioeconomic status with kidney function were studied cross-sectionally and longitudinally among 736 community-dwelling African Americans who were aged >65 yr and participating in the Cardiovascular Health Study. Genetic African ancestry was determined by genotyping 24 biallelic ancestry-informative markers and combining this information statistically to generate an estimate of ancestry for each individual. Kidney function was evaluated by cystatin C and estimated GFR (eGFR) using the Modification of Diet in Renal Disease equation. Longitudinal changes in serum creatinine and eGFR were estimated using baseline and follow-up values. In cross-sectional analyses, there was no association between genetic African ancestry and either measure of kidney function (P = 0.36 for cystatin C and 0.68 for eGFR). African ancestry was not associated with change in serum creatinine > or =0.05 mg/dl per yr (odds ratio [OR] 0.94; 95\% confidence interval [CI] 0.83 to 1.06) or with change in eGFR > or =3 ml/min per 1.73 m(2) per yr (OR 1.02; 95\% CI 0.92 to 1.13). In contrast, self reported African-American race was strongly associated with increased risk for kidney disease progression compared with white individuals for change in creatinine (OR 1.77; 95\% CI 1.33 to 2.36) and for change in eGFR (OR 3.21; 95\% CI 2.54 to 4.06). Among self-identified African Americans, low income (< US dollars 8000/yr) was strongly associated with prevalent kidney dysfunction by cystatin C >1.29 g/dl (adjusted OR 2.7; 95\% CI 1.0 to 7.5) or by eGFR <60 ml/min per 1.73 m(2) (adjusted OR 3.2; 95\% CI 1.1 to 9.4) compared with those with incomes >US dollars 35,000/yr. Alleles that are known to be present more frequently in the African ancestral group were not associated with kidney dysfunction or kidney disease progression. Rather, kidney dysfunction in elderly African Americans seems more attributable to differences in environmental and social factors.

}, keywords = {African Americans, Aged, Creatinine, Cross-Sectional Studies, Cystatin C, Cystatins, Disease Progression, Female, Glomerular Filtration Rate, Humans, Kidney Diseases, Linear Models, Longitudinal Studies, Male, Social Class}, issn = {1046-6673}, doi = {10.1681/ASN.2006050493}, author = {Peralta, Carmen A and Ziv, Elad and Katz, Ronit and Reiner, Alex and Burchard, Esteban Gonz{\'a}lez and Fried, Linda and Kwok, Pui-Yan and Psaty, Bruce and Shlipak, Michael} } @article {986, title = {Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {197}, year = {2008}, month = {2008 Apr}, pages = {922-30}, abstract = {

Common polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95\% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.

}, keywords = {African Americans, Aged, C-Reactive Protein, Cardiovascular Diseases, Cause of Death, Cohort Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Linear Models, Longevity, Male, Polymorphism, Single Nucleotide, Proportional Hazards Models, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2007.08.012}, author = {Hindorff, Lucia A and Rice, Kenneth M and Lange, Leslie A and Diehr, Paula and Halder, Indrani and Walston, Jeremy and Kwok, Pui and Ziv, Elad and Nievergelt, Caroline and Cummings, Steven R and Newman, Anne B and Tracy, Russell P and Psaty, Bruce M and Reiner, Alexander P} } @article {1104, title = {Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity.}, journal = {Aging Cell}, volume = {8}, year = {2009}, month = {2009 Aug}, pages = {460-72}, abstract = {

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95\%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95\%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.

}, keywords = {Aged, Aged, 80 and over, Female, Follow-Up Studies, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome, Human, Genotype, Humans, Insulin, Insulin-Like Growth Factor I, Longevity, Male, Osteoporosis, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-akt, Signal Transduction}, issn = {1474-9726}, doi = {10.1111/j.1474-9726.2009.00493.x}, author = {Pawlikowska, Ludmila and Hu, Donglei and Huntsman, Scott and Sung, Andrew and Chu, Catherine and Chen, Justin and Joyner, Alexander H and Schork, Nicholas J and Hsueh, Wen-Chi and Reiner, Alexander P and Psaty, Bruce M and Atzmon, Gil and Barzilai, Nir and Cummings, Steven R and Browner, Warren S and Kwok, Pui-Yan and Ziv, Elad} } @article {1081, title = {Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.}, journal = {Exp Gerontol}, volume = {44}, year = {2009}, month = {2009 May}, pages = {350-5}, abstract = {

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15\%-20\% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95\%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

}, keywords = {Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Case-Control Studies, Female, Genetic Variation, Genotype, Humans, Inflammation, Interleukin-6, Longevity, Male, Phenotype, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, Risk Factors}, issn = {1873-6815}, doi = {10.1016/j.exger.2009.02.004}, author = {Walston, Jeremy D and Matteini, Amy M and Nievergelt, Caroline and Lange, Leslie A and Fallin, Dani M and Barzilai, Nir and Ziv, Elad and Pawlikowska, Ludmila and Kwok, Pui and Cummings, Steve R and Kooperberg, Charles and LaCroix, Andrea and Tracy, Russell P and Atzmon, Gil and Lange, Ethan M and Reiner, Alex P} } @article {1218, title = {Genetic ancestry in lung-function predictions.}, journal = {N Engl J Med}, volume = {363}, year = {2010}, month = {2010 Jul 22}, pages = {321-30}, abstract = {

BACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.

METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.

RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5\% of participants.

CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)

}, keywords = {Adolescent, Adult, African Americans, Aged, Aged, 80 and over, Female, Forced Expiratory Volume, Genetic Markers, Genotype, Humans, Linear Models, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Reference Values, Respiratory Function Tests, Vital Capacity, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa0907897}, author = {Kumar, Rajesh and Seibold, Max A and Aldrich, Melinda C and Williams, L Keoki and Reiner, Alex P and Colangelo, Laura and Galanter, Joshua and Gignoux, Christopher and Hu, Donglei and Sen, Saunak and Choudhry, Shweta and Peterson, Edward L and Rodriguez-Santana, Jose and Rodriguez-Cintron, William and Nalls, Michael A and Leak, Tennille S and O{\textquoteright}Meara, Ellen and Meibohm, Bernd and Kritchevsky, Stephen B and Li, Rongling and Harris, Tamara B and Nickerson, Deborah A and Fornage, Myriam and Enright, Paul and Ziv, Elad and Smith, Lewis J and Liu, Kiang and Burchard, Esteban Gonz{\'a}lez} } @article {6090, title = {Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Dec 15}, pages = {5385-94}, abstract = {

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 {\texttimes} 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 {\texttimes} 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 {\texttimes} 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 {\texttimes} 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

}, keywords = {Genome-Wide Association Study, Humans, Kruppel-Like Transcription Factors, Telomere, Telomere Homeostasis, Telomere-Binding Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/dds382}, author = {Mangino, Massimo and Hwang, Shih-Jen and Spector, Timothy D and Hunt, Steven C and Kimura, Masayuki and Fitzpatrick, Annette L and Christiansen, Lene and Petersen, Inge and Elbers, Clara C and Harris, Tamara and Chen, Wei and Srinivasan, Sathanur R and Kark, Jeremy D and Benetos, Athanase and El Shamieh, Said and Visvikis-Siest, Sophie and Christensen, Kaare and Berenson, Gerald S and Valdes, Ana M and Vi{\~n}uela, Ana and Garcia, Melissa and Arnett, Donna K and Broeckel, Ulrich and Province, Michael A and Pankow, James S and Kammerer, Candace and Liu, Yongmei and Nalls, Michael and Tishkoff, Sarah and Thomas, Fridtjof and Ziv, Elad and Psaty, Bruce M and Bis, Joshua C and Rotter, Jerome I and Taylor, Kent D and Smith, Erin and Schork, Nicholas J and Levy, Daniel and Aviv, Abraham} } @article {6594, title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {1026-32}, abstract = {

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95\% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95\% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 {\textpm} 0.20 versus 1.02 {\textpm} 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

}, keywords = {Age Factors, Aged, Aging, Atrial Fibrillation, California, Cardiac Surgical Procedures, Cellular Senescence, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Incidence, Leukocytes, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Telomerase, Telomere, Time Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001781}, author = {Roberts, Jason D and Dewland, Thomas A and Longoria, James and Fitzpatrick, Annette L and Ziv, Elad and Hu, Donglei and Lin, Jue and Glidden, David V and Psaty, Bruce M and Burchard, Esteban G and Blackburn, Elizabeth H and Olgin, Jeffrey E and Heckbert, Susan R and Marcus, Gregory M} } @article {7165, title = {Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.}, journal = {JAMA Cardiol}, volume = {1}, year = {2016}, month = {2016 Jul 1}, pages = {442-50}, abstract = {

IMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.

OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.

DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.

MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.

RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4\%; 95\% CI, 2.9\%-29.9\%) and ARIC (31.7\%; 95\% CI, 16.0\%-53.0\%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.

CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2016.1185}, author = {Roberts, Jason D and Hu, Donglei and Heckbert, Susan R and Alonso, Alvaro and Dewland, Thomas A and Vittinghoff, Eric and Liu, Yongmei and Psaty, Bruce M and Olgin, Jeffrey E and Magnani, Jared W and Huntsman, Scott and Burchard, Esteban G and Arking, Dan E and Bibbins-Domingo, Kirsten and Harris, Tamara B and Perez, Marco V and Ziv, Elad and Marcus, Gregory M} }