Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels – a study in twins

Abstract

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD. Genes and Immunity (2006) Keywords: twin pairs; heritability; interleukin-6; C-reactive protein; body mass index Low-grade inflammation is thought to play an essential role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD) events. 1,2 As a highly sensitive C-reactive protein (CRP) measurement is possible, several large epidemiological studies have demonstrated association between elevated plasma CRP levels reflecting low-grade inflammation and the development of CVD events such as coronary heart disease (CHD), stroke or peripheral arterial disease. 3-7 CRP represents not only a sensitive marker for systemic inflammation, but also contributes to the complex interaction occurring between endothelial dysfunction, lipid accumulation, cell activation and inflammatory response in the pathogenesis of atherosclerosis. [8][9][10][11] Family studies have suggested that 35-45% of the variations in plasma baseline CRP levels are genetically determined [12][13][14][15] and twin studies revealed a heritability of 20-52% for CRP. [16][17][18] In addition, it is known that (environmental) factors such as obesity, older age, female gender, smoking, diabetes mellitus, chronic infections, lower socio-economic status, greater alcohol consumption and medications such as oral contraceptives are involved in a low-grade inflammatory response with elevated plasma CRP levels. 6,[19][20][21][22][23][24][25][26] An aim of determining plasma CRP levels could be related to polymorphisms in upstream cytokines such as interleukin (IL)-6. 13,27 IL-6 induces CRP production in hepatocytes and it is the only cytokine that can stimulate the synthesis of all other acute-phase proteins. [28][29][30] Thus, some authors proposed IL-6 as a useful prognostic marker of CVD outcome 31-37 and suggested a central role for IL-6 in the pathogenesis of CHD. [38][39][40] However, the estimated heritability for IL-6 ranged between 0.17 and 0.57 in the literature 16,41,42 and previous studies concerning the heritability of CRP and IL-6 have to be interpreted carefully (Table 1). The design and exact an...

Heritability of serum hs-CRP concentration and 5-year changes in the Stanislas family study: association with apolipoprotein E alleles

“…Heritability of serum hs-CRP concentration H Berrahmoune et al discrepancy between most of the previous familial and twin studies investigating the hs-CRP concentration heritability and our results, since they reported a significant and higher polygenic effect (between 20 and 52%) [8][9][10]12,13 (Table 5), while we found no genetic effect on hs-CRP concentration heritability. However, our results are in accordance with those of Friedlander et al 15 who reported no polygenic effect for hs-CRP concentrations and the changes of over 10 years.…”

“…In twin studies, within-pair correlations were even higher: 0.40-0.49 and 0.17-0.28, for MZ, 9,10,30 and DZ twins, 9,10 respectively. In addition, there is a Tables A2 and A3 in online appendix.…”

“…7 In view of the importance of hs-CRP concentration, several teams investigated its genetic heritability in various populations of middle-aged adults or elderly. The twin studies estimated genetic heritability ranged between 22 and 56%, [8][9][10][11] while studies based on individuals from large pedigrees showed that polygenic component accounted for lower values (between 28 and 39% of total variance). [12][13][14] However, a recent family study concluded to have no polygenic effect in heritability of hs-CRP level.…”

Genetic Architecture of the Pro-Inflammatory State in an Extended Twin-Family Design

“…The most parsimonious model is printed in bold. Jermendy et al, 2011;MacGregor et al, 2004;Rahman et al, 2009;Reed et al, 1994;Sas et al, 2012;Su et al, 2008Su et al, , 2009aSu et al, , 2009bWang et al, 2011;Wessel et al, 2007;Worns et al, 2006) and extend the findings of previous studies by showing that genetic non-additivity is an important factor in explaining individual differences in TNF-␣, CRP, and fibrinogen levels and by ruling out a large role for environmental factors shared by family members.…”

Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus

“…3 A large proportion of this heritability can be explained by the IL6R polymorphism, rs2228145 (previously rs8192284 or D358A), which affects both circulating soluble IL-6R and IL-6 levels, 4-6 but this does not account for all the reported heritability (up to 0.61). 7 The IL6 promoter has been extensively studied in terms of both transcription factor binding and genetic variation, with a number of well-characterised polymorphisms identified in the proximal promoter, including rs1800795 ( À 174G4C), rs1800796 ( À 572G4C) and rs1800797 ( À 597G4A). Despite the numerous association studies with these single-nucleotide polymorphisms (SNPs), and studies on in vivo circulating IL-6 levels, in vitro gene expression and luciferase reporter assays (reviewed in Smith and Humphries 3 ), there is no conclusive evidence of IL6-SNP functionality.…”