Additive effect of interleukin-6 and C-reactive protein (CRP) single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors

Background: Serum C-reactive protein (CRP) levels, closely associated with cardiovascular disease (CVD) risk are influenced by CRP or interleukin-6 (IL-6) single nucleotide polymorphism (SNPs). However, it is still controversial. Therefore, we investigated the association of IL-6/CRP SNPs and serum CRP levels or other CVD risk factors in healthy adult Korean men. Methods: In healthy adult men (age ≥ 20 years, n = 677), we genotyped IL-6-572C > G and CRP SNPs (- 717G > A, 1444C > T, 2147A > G) and measured anthropometric parameters, lipid profile, serum levels of CRP and IL-6 and insulin resistance. Results: At IL-6-572C > G (n = 677), subjects with G/G genotype (n = 42) showed higher concentrations of CRP (P = 0.027) and IL-6 (P = 0.028) as compared with C allele carriers after age-adjustment (C/C: n = 371, C/G: n = 264). Fasting insulin and homeostatis model assessment insulin resistance (HOMA-IR) were also higher in G/G genotype. However, there were no significant differences in other metabolic biomarkers. Among 677 study subjects, 676 were genotyped at CRP-717G > A (G/G: n = 513, G/A: n = 150, A/A: n = 13), 672 at CRP+1444C > T (C/C: n = 580, C/T: n = 85, T/T: n = 7), and 668 at CRP+2147A > G (A/A: n = 273, A/G: n = 296, G/G: n = 99). There were no significant differences in CRP concentrations and other markers related to CVD risk according to each CRP SNP genotype. However, we could find the additive gene-gene interaction between IL-6-572C > G and CRP SNPs on CRP concentration; subjects with the 'G/G' at IL-6-572 showed the highest CRP levels when they have variant allele at CRP SNPs after adjusted for age, body mass index, cigarette smoking and alcohol drinking (- 717G > A: F = 7.806, P = 0.005; CRP + 1444C > T: F = 8.398, P = 0.004; and CRP + 2147A > G: F = 7.564, P = 0.006, respectively) Particularly, G allele carriers at CRP+2147A > G in subjects with IL-6-572G/G showed highest HOMA-IR (F = 9.092, P = 0.003). Conclusion: The present data showed that serum CRP levels and other CVD risk factors appeared more influenced by IL-6-572C > G rather than CRP SNPs (- 717G > A, 1444C > T, and 2147A > G), however CRP levels and insulin resistance may be additively affected by IL-6-572 and CRP SNP, particularly when subjects with G/G genotype at IL-6-572 have allele variant at CRP SNPs.