@article {982, title = {IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.}, journal = {Hum Genet}, volume = {122}, year = {2007}, month = {2007 Dec}, pages = {485-94}, abstract = {

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95\% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95\% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

}, keywords = {African Americans, Aged, Alleles, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Humans, Interleukin-6, Introns, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-007-0428-x}, author = {Walston, Jeremy D and Fallin, M Daniele and Cushman, Mary and Lange, Leslie and Psaty, Bruce and Jenny, Nancy and Browner, Warren and Tracy, Russell and Durda, Peter and Reiner, Alex} } @article {1347, title = {Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.}, journal = {Circ Cardiovasc Genet}, volume = {4}, year = {2011}, month = {2011 Dec}, pages = {661-72}, abstract = {

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 {\texttimes} 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 {\texttimes} 10(-6)), MTHFD1L (rs6922269, P=5.1 {\texttimes} 10(-10)), APOE (rs429358; P=2.7{\texttimes}10(-18)), ZNF627 (rs4804611; P=5.0 {\texttimes} 10(-8)), CXCL12 (rs501120; P=1.4 {\texttimes} 10(-6)) and LPL (rs268; P=2.7 {\texttimes} 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

}, keywords = {Aged, Aged, 80 and over, Continental Population Groups, Coronary Disease, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.960096}, author = {Franceschini, Nora and Carty, Cara and B{\r u}zkov{\'a}, Petra and Reiner, Alex P and Garrett, Tiana and Lin, Yi and V{\"o}ckler, Jens-S and Hindorff, Lucia A and Cole, Shelley A and Boerwinkle, Eric and Lin, Dan-Yu and Bookman, Ebony and Best, Lyle G and Bella, Jonathan N and Eaton, Charles and Greenland, Philip and Jenny, Nancy and North, Kari E and Taverna, Darin and Young, Alicia M and Deelman, Ewa and Kooperberg, Charles and Psaty, Bruce and Heiss, Gerardo} } @article {1349, title = {Kidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2).}, journal = {Am J Nephrol}, volume = {34}, year = {2011}, month = {2011}, pages = {512-8}, abstract = {

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 {\textpm} 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}, issn = {1421-9670}, doi = {10.1159/000333045}, author = {Peralta, Carmen A and Katz, Ronit and Shlipak, Michael and Dubin, Ruth and DeBoer, Ian and Jenny, Nancy and Fitzpatrick, Annette and Koro, Carol and Kestenbaum, Bryan and Ix, Joachim and Sarnak, Mark and Cushman, Mary} } @article {6634, title = {Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35651}, abstract = {

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 {\texttimes} 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 {\texttimes} 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}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035651}, author = {Buyske, Steven and Wu, Ying and Carty, Cara L and Cheng, Iona and Assimes, Themistocles L and Dumitrescu, Logan and Hindorff, Lucia A and Mitchell, Sabrina and Ambite, Jose Luis and Boerwinkle, Eric and B{\r u}zkov{\'a}, Petra and Carlson, Chris S and Cochran, Barbara and Duggan, David and Eaton, Charles B and Fesinmeyer, Megan D and Franceschini, Nora and Haessler, Jeffrey and Jenny, Nancy and Kang, Hyun Min and Kooperberg, Charles and Lin, Yi and Le Marchand, Lo{\"\i}c and Matise, Tara C and Robinson, Jennifer G and Rodriguez, Carlos and Schumacher, Fredrick R and Voight, Benjamin F and Young, Alicia and Manolio, Teri A and Mohlke, Karen L and Haiman, Christopher A and Peters, Ulrike and Crawford, Dana C and North, Kari E} } @article {6608, title = {Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {165-73}, abstract = {

BACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.

METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95\% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95\% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.

CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cohort Studies, Female, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Interleukin-6, Longevity, Male, Receptors, Tumor Necrosis Factor, Type I, Risk Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt023}, author = {Varadhan, Ravi and Yao, Wenliang and Matteini, Amy and Beamer, Brock A and Xue, Qian-Li and Yang, Huanle and Manwani, Bhavish and Reiner, Alexander and Jenny, Nancy and Parekh, Neel and Fallin, M Daniele and Newman, Anne and Bandeen-Roche, Karen and Tracy, Russell and Ferrucci, Luigi and Walston, Jeremy} }