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Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.

Jeremy D. Walston, Amy M. Matteini, Caroline Nievergelt, Leslie A. Lange, Dani M. Fallin, Nir Barzilai, Elad Ziv, Ludmila Pawlikowska, Pui Kwok, Steve R. Cummings, Charles Andrea LaCroix, Russell P. Tracy, Gil Atzmon, Ethan M. Lange, and Alex P. Reiner.

Hopkins Medical Institutions, Johns Hopkins University, John R Burton Pavilion, 5505 Hopkins Bayview Circle of California at San Diego, San Diego, CA, USA of North Carolina, Chapel Hill, NC, USA of Vermont, Colchester VT., USA of Medicine Albert Einstein College of Medicine Bronx NY., USA of California at San Francisco San Francisco CA., USA Hutchinson Cancer Research Center Seattle WA., USA of Epidemiology University of Washington Box 357236 Seattle WA 98195 USA.

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.

2009 Elsevier Inc. All rights reserved.

Introduction:

Aging is associated with low-grade elevation of circulating inflammatory markers (Franceschi et al., 2007; Vasto et al., 2007). Interleukin-6 (IL-6) is a multi-functional inflammatory cytokine that plays an important role in the response to environmental stress and has been implicated in the pathogenesis of many chronic diseases associated with aging (Ershler and Keller, 2000). Increased circulating levels of IL-6 have been associated with the subsequent occurrence of coronary heart disease (Danesh et al., 2008) as well as with physical disability, frailty, increased all-cause and disease-specific mortality and decreased longevity in older adults (Harris et al., 1999; Ferrucci et al., 1999; Volpato et al., 2001; Reuben et al., 2002; Roubenoff et al., 2003; Cohen et al., 2003; Penninx et al., 2004; Strk et al., 2006; Heikkil et al., 2007). While increased IL-6 levels may signal the occurrence of underlying pathological mechanisms, IL-6 may also contribute directly to a wide variety of chronic degenerative processes, including atherosclerosis (Huber et al., 1999; Ershler and Keller, 2000). 

Circulating IL-6 levels (de Maat et al., 2004; de Craen et al., 2005; Dupuis et al., 2005; Su et al., 2008; Wrns et al., 2006) and lifespan (vB Hjelmborg et al., 2006) are likely heritable traits in older adults, although specific genetic factors responsible for inter-individual differences in IL-6 levels and human longevity are largely unknown. Determination of specific contributing variants to IL-6 and longevity is difficult, in part because of the complexity of inflammatory signaling, and because populations studied to date were not recruited for the study of longevity or inflammatory phenotypes. A common promoter variant of the IL6 gene, (174 G/C) (rs1800795), was found to be weakly associated with plasmaFollow-up data for the CHS cohort were available through June 2005. Fatal events due to all causes were defined and adjudicated by physician review, according to medical records and death certificates. The National Death Index provided complete mortality follow-up. The cause of death was adjudicated using published criteria: cardiovascular disease (CVD) death was defined as death due to atherosclerotic coronary heart disease, cerebrovascular disease, atherosclerotic disease, or other CVD (Ives et al., 1995). For our candidate gene longevity phenotype association analysis, we defined long-lived cases as subjects who lived to at least 92 years of age (n = 479; 61% female) and shorter-lived controls as subjects who died before the age of 79 years (n = 900; 46% female).

Candidate genes were genotyped by the Center for Inherited Disease Research (CIDR) using the Illumina GoldenGate 1536 SNP platform. The overall genotype missing rate was <0.1%; the genotyping failure rate did not exceed 4.2% for any of the SNPs under study. Concordance rates for blind duplicate samples were >99.5% for all SNP assays across both genotyping platforms. We excluded SNPs from analysis with minor allele frequency less than 5%. Using this procedure, we identified 477 and 727 tagSNP bins among EAs and AAs, respectively, across 87 candidate genes. Of the total number of tagSNPs analyzed (n = 791), 413 or 52% were common to both EA and AA, while 64 and 314 were unique to EA and AA, respectively.

2.2. Centenarian case-control study of Ashkenazi Jews