Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero   {|[! galExperimentalGerontology

journal homepage: www.elsevier.com/locate/expgero

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

Jeremy D. Walston a, *, Amy M. Matteini a, Caroline Nievergelt b, Leslie A. Lange c, Dani M. Fallin a, Nir Barzilai e, Elad Ziv f, Ludmila Pawlikowska f, Pui Kwok f, Steve R. Cummings f, Charles Andrea LaCroix g, Russell P. Tracy d, Gil Atzmon e, Ethan M. Lange c, Alex P. Reiner h, *

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

a b s t r a c t

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 base- line IL-6 concentration per copy among CHS European–American (EA) participants (all p < 10(cid:2)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 longev- ity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62–1.02; p = 0.07). These find- ings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

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1. Introduction

2001; Reuben et al., 2002; Roubenoff et al., 2003; Cohen et al 2003; Penninx et al., 2004; Störk et al., 2006; Heikkilä et al., 2007). While increased IL-6 levels may signal the occurrence of underlying pathological mechanisms, IL-6 may also contribute di- rectly to a wide variety of chronic degenerative processes, includ- ing atherosclerosis (Huber et al., 1999; Ershler and Keller, 2000).

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 cyto- kine 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.,

Circulating IL-6 levels (de Maat et al., 2004; de Craen et al., 2005; Dupuis et al., 2005; Su et al., 2008; Wörns et al., 2006) and life span (vB Hjelmborg et al., 2006) are likely heritable traits in older adults, although specific genetic factors responsible for in- ter-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 phe- notypes. A common promoter variant of the IL6 gene, (cid:2)174 G/C (rs1800795) was found to be weakly associated with plasma IL-6 levels and CRP levels in older adults, but was not associated with

* Corresponding authors. Tel.: +1 410 550 1003; fax: +1 410 550 2513 (J.D. Walston); tel.: +1 206 685 9062; fax: +1 206 543 8525 (A.P. Reiner). E-mail addresses: jwalston@jhmi.edu (J.D. Walston), apreiner@u.washington.edu (A.P. Reiner).

mortality (Walston et al., 2007). In a recent meta-analysis of eight European case-control studies, there was no significant overall dif- ference in IL-6 genotype frequencies between long-lived and con- trols, though the (cid:2)174 GG genotype was less common in a subgroup of Italian male centenarians (Di Bona et al., 2009). Given the evidence for genetic influence on IL-6 levels, we hypothesized that polymorphisms in additional inflammation or stress-response genes may account for inter-individual variation in plasma IL-6 concentration and may also contribute to human longevity. In or- der to test this hypothesis, we designed a candidate gene study that utilized a large cohort study of older adults and two additional nested case-control samples of older adults for validation as de- scribed below.

2003; Atzmon et al., 2006; Suh et al. 2008; Atzmon et al., 2008). In- formed written consent was obtained in accordance with the pol- icy of the Committee on Clinical Investigations of the Albert Einstein College of Medicine.

2.3. Study of Osteoporotic Fractures (SOF)