Effect of interleukin-6 polymorphisms on human longevity: A systematic review and meta-analysis

Abstract

Several studies have assessed changes in frequency of −174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozgyous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case–control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio [OR] = 0.96; 95% C.I.: 0.77–1.20; p = 0.71), but there was significant between-study heterogeneity (I² = 55.5%). In a subgroup analyses when male centenarians from the three Italian studies were included, the frequency of the IL-6 −174 GG genotype was significantly lower than the other genotypes (OR = 0.49; 95% C.I.: 0.31–0.80; p = 0.004), with no evidence of heterogeneity (I² = 0%). Our data supports a negative association between the GG genotype of IL-6 SNP and longevity in Italian centenarians, with males who carry the genotype being two times less likely to reach extreme old age compared with subjects carrying CC or CG genotypes. These findings were not replicated in other European groups suggesting a possible interaction between genetics, sex and environment in reaching longevity.

Introduction

Ageing has been associated with a chronic low-grade inflammation, which appears to be responsible for the development of age-related diseases, such as atherosclerosis, dementia, and type II diabetes, all of which lead to increased mortality (Krabbe et al., 2004, Bruunsgaard, 2006, Vasto et al., 2007a, Vasto et al., 2007b, Vasto et al., 2008). Cytokines are believed to play a pivotal role in the regulation of the type and magnitude of the immune-inflammatory responses and may therefore play a key role in ageing and survival (Caruso et al., 2007)

Interleukin (IL)-6 is a pleiotropic cytokine capable of regulating proliferation, differentiation and activity in a variety of cell types (Ershler and Keller, 2000). It plays a major role in bone remodelling, neuro-endocrine homeostasis, haemopoiesis and immune-inflammatory response regulation. In particular, IL-6 plays a pivotal role in acute phase responses and in the balancing of the pro-inflammatory/anti-inflammatory pathways (Ershler and Keller, 2000). IL-6, involved in impaired lipid metabolism and in the production of triglycerides, decreases lipoprotein lipase activity and monomeric lipoprotein lipase levels in plasma which contributes to increased macrophage uptake of lipids. In fatty streaks and in the atheromatous ‘cap’ and ‘shoulder’ regions, macrophage foam cells and smooth muscle cells express IL-6 suggesting a role for this cytokine in the progression of atherosclerosis. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal axis, activation of which is associated with central obesity, hypertension and insulin resistance (ref. in Candore et al., 2006a, Rea et al., 2006).

The IL-6 gene, located in humans in the short arm of chromosome 7 (7p21), displays a single nucleotide polymorphism (SNP) in the promoter region (−174 G/C) which seems to be associated to variations of IL-6 gene expression and serum levels (Fishman et al., 1998). Increased IL-6 levels occur in GG genotype both in ‘in vitro’ and ‘in vivo’ studies (Fishman et al., 1998, Hoffmann et al., 2001, Olivieri et al., 2002, Bennermo et al., 2004, Bonafe et al., 2001, Giacconi et al., 2004), although a few authors report increased IL-6 values in CC genotype (Haddy et al., 2005, Jerrard-Dunne et al., 2003). However, it must be noted that IL-6 has a short half-life and is complex to assay (Neal, 2008).

Serum IL-6 has been proposed as a reliable marker for functional decline, as a predictor of morbidity and mortality in old age, and increases in IL-6 have been associated with functional disability, cognitive decline and stroke in older people (Barbieri et al., 2003, Cesari et al., 2004, Ershler and Keller, 2000). If IL-6 tracks with disability and age-related disease then there should be a reduced frequency of GG homozygotes, associated with higher IL-6 levels, in the oldest old. The results of studies to date have however been conflicting (ref. in Candore et al., 2006a, Rea et al., 2006, Vasto et al., 2007a) with Bonafe et al., 2001 finding the frequency of GG homozygotes of IL-6 −174 C/G polymorphism reduced in centenarians and in long-lived subjects whereas a more recent study found opposite results (Christiansen et al., 2004). The majority of the other published genetic studies on the association between this IL-6 SNP and longevity failed to show either a significant positive or negative association (ref. in Rea et al., 2006). The lack of replicability between different studies may relate to the heterogeneity of the enrolled study populations and the small sample size of some studies, resulting in reduced statistical power (Lohmueller et al., 2003).

Meta-analysis has become an important research tool in reconciling previously conducted studies with inconsistent results and so in the present study, we performed a meta-analysis of case–control studies on the association between IL-6 −174 SNP and longevity. Our aim was to explore the role of this polymorphism in the attainment of longevity and to explain the possible reasons for inconsistency in replication of the results between studies.