Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults
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, 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 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, 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 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 plasma IL-6 levels and CRP levels in older adults, but was not associated with mortality (Walston et al., 2007). In a recent meta-analysis of eight European case-control studies, there was no significant overall difference in IL-6 genotype frequencies between long-lived and controls, though the −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 order 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 described below.
Section snippets
The Cardiovascular Health Study (CHS)
In order to test our hypothesis in the larger candidate gene panel, we utilized stored DNA and previously measured and collected data from CHS. CHS is a prospective, population-based cohort study of 5888 adult men and women 65 y and older recruited from four field centers: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania (Fried et al., 1991). Baseline examination for the original cohort, of whom 4925 or 95% self-identified
Baseline IL-6 levels predict all-cause mortality in CHS
CHS participant baseline characteristics by race are summarized in Table 1. In univariate and multivariable-adjusted regression analyses, older age, male sex, current smoking, higher BMI, alcohol consumption, and prevalent CVD were significantly associated with higher IL-6 (all p < 0.001). When analyzed by quartiles, and adjusted for other risk factors, baseline IL-6 levels were strongly and independently associated with a linear increase in all-cause mortality, as well as mortality due to
Discusssion
Our results confirm that higher circulating IL-6 levels strongly predict future mortality in a large community-based sample of older EA and AA adults from CHS. By screening a panel of inflammation and stress-response candidate genes, we demonstrate that SNPs tagging common functional polymorphisms of IL6R and PARP1 are associated with circulating IL-6 levels among European–American CHS participants. Though no SNPs contained within our candidate gene panel reached the experiment-wide
Acknowledgments
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
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