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.
Bibliographical noteFunding Information:
This study was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, N01-HC-45133, Grant No. U01 HL080295 from the National Heart, Lung, and Blood Institute, U19 AG023122 from the National Institute on Aging Longevity Consortium and P30 AG021334 from the National Institute on Aging Claude D. Pepper Older Americans Independence Centers, and grants R01 AG027236 (Dr. Walston), R01 HL-071862 (Dr Reiner), R01 HL077449 (Dr. Tracy), P01 AG027734 (Dr. Atzmon) and U01 HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org . Genotyping services for CHS were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. Genotyping services for CHS were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from the National Heart, Lung, and Blood Institute. We utilized public re-sequencing data from the SeattleSNPs program, supported by NIH U01 HL66682 ( http://www.pga.gs.washington.edu/ ). This work has also been supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, NIH RO1 (AG-18728–01A1).
- Genetic epidemiology
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology