Associations between inflammatory markers, candidate polymorphisms and physical performance in older Danish twins

Abstract

Inflammation may play an essential role in the decline of physical performance. In this study we investigated the associations between inflammatory markers, candidate polymorphisms and physical performance in elderly people. Plasma levels of TNF-α, IL-6, CRP, fibrinogen, sICAM-1 and candidate polymorphisms were measured in 600 twin individuals aged 73 years and older participating in the Longitudinal Study of Aging Danish Twins. Physical performance was assessed using a self-reported measure. The inclusion of twins allowed both traditional and within-twin-pair analysis which permitted control for shared environment and genetic factors. Higher levels of inflammatory markers were generally associated with a lower level of physical performance. The TNFα-238G/A polymorphism was significantly associated with physical performance in men, with A allele carriers having significantly better performance than GG homozygotes. However, this gene variation seems to have only a minor role in explaining the associations between the levels of inflammatory markers and physical performance. When using twin pair analysis to test whether genetic factors in general account for this association, results showed that the association between the level of fibrinogen and physical performance could be caused by genetic factors. Also the association between the level of TNF-α and physical performance in males could be caused by genetic factors. However, other gene variations than the candidate gene polymorphisms studied here seem to explain the major part of the genetic proportion of this association.

Introduction

The decline of physical performance is a multifactorial phenomenon which contains many different factors such as physiological age-related changes in muscle mass and muscle strength (Strotmeyer et al., 2009, Leveille, 2004), balance impairments and increased risk of falling (Tiedemann et al., 2008), decreased resistance to fatigue (Vestergaard et al., 2009), and decreased physical activity (Buchman et al., 2007), and an increased number of chronic diseases (Hopman et al., 2009).

Elevated plasma/serum levels of inflammatory markers are known to be associated with many different diseases such as cardiovascular diseases (Danesh et al., 2008), diabetes mellitus (Dehghan et al., 2007), Alzheimer disease (Holmes et al., 2009), osteoporosis (McCormick, 2007), and also with mortality and shorter life expectancy (Jylhä et al., 2007, Bruunsgaard et al., 2003). The concentration of inflammatory markers also tends to increase with advancing age (Ferrucci et al., 2005).

Recent studies have demonstrated that inflammation may play an important role in the process of aging and in the development of functional limitations and disabilities (Ferrucci et al., 2002, Cesari et al., 2004, Visser et al., 2002, Tiainen et al., 2010, Brinkley et al., 2009). Elevated levels of inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been associated with poor muscle strength(Ferrucci et al., 2002, Cesari et al., 2004, Brinkley et al., 2009, Stenholm et al., 2010) and decline in physical performance such as decreased walking speed and a longer time required for chair rise (Ferrucci et al., 2002, Cesari et al., 2004, Visser et al., 2002, Brinkley et al., 2009). Tumor necrosis factor-α (TNF-α) has a strong catabolic effect on muscle (Reid and Li, 2001) and it is associated with low muscle mass and muscle strength (Visser et al., 2002, Schaap et al., 2009, Bautmans et al., 2005) and with a steeper decline in muscle strength over time (Taekema et al., 2007). Elevated levels of fibrinogen are an important cardiovascular risk factor, but also increase risk of frailty (Walston et al., 2002).

Inflammatory marker production and the regulation of protein levels are believed to be partly genetically controlled (de Maat et al., 2004). However, results on the influence of commonly studied variations in relevant genes have been conflicting. In this study we evaluated the possible effects of some of the most repeatedly considered candidate polymorphisms of inflammatory marker genes for which associations with gene expression or protein levels of inflammatory markers have been demonstrated. We therefore included the IL6-174G/C polymorphism, which has been associated with concentrations of IL-6 (Fishman et al., 1998, Giacconi et al., 2004, Bonafe et al., 2001, Bruunsgaard et al., 2004); the CRP-1059G/C polymorphism, which has an effect on CRP levels (Vickers et al., 2002, Suk et al., 2005, Motoyama et al., 2009); the TNFα-238G/A polymorphism for which an influence on TNF-α gene expression has been shown (Huizinga et al., 1997) and the ICAM1-469K/E polymorphism suggested as a candidate variation within degenerative and inflammatory diseases (Amoli et al., 2002, Jiang et al., 2002). Finally, the fibrinogen-455G/A polymorphism has repeatedly been associated with plasma fibrinogen levels among middle-aged men and women (Tybjaerg-Hansen et al., 1997, van 't Hooft, et al., 1999).

Because these gene polymorphisms have been suggested to partly regulate the levels of inflammatory markers and since the levels of inflammatory markers are associated with physical performance, it may be hypothesized that these polymorphisms are also associated with variation in physical performance.

Accordingly, the aim of this study was to examine the associations between CRP, IL-6, TNF-α, soluble intercellular adhesion molecule-1 (sICAM-1), and fibrinogen and physical performance in old age using a cohort of older Danish twins, and to investigate if candidate gene polymorphisms (CRP-1059G/C, IL6-174C/T, TNFα-238G/A, ICAM1-469K/E, fibrinogen-455G/A) could in part explain this association.