Because recent genome-wide association studies (GWAS) have shown a relationship between common variants in the interleukin-6 (IL-6) receptor (IL6R) gene and C-reactive protein (CRP) concentrations and because IL6R variants have also been shown to be associated with IL-6 concentrations, this study investigated whether the associations between IL6R variants and CRP levels were independent of IL-6 concentrations. This study also examined the interactions between IL6R variants and CRP in relation to diabetes risk in a case-control study of 633 diabetic and 692 healthy Caucasian women. In both diabetic and control subjects, IL6R polymorphisms were associated with CRP concentrations independently of IL-6 levels. Because SNP rs8192284 was a missense variant related to CRP in the GWAS that showed the strongest association with IL-6 concentrations, the interactions between this SNP and CRP levels in relation to diabetes risk were investigated. In this analysis, rs8192284 showed significant interactions with CRP in relation to diabetes risk. After adjusting for covariates (including IL-6 levels), odds ratios across increasing quartiles of CRP were 2.21 (95% CI: 1.18-4.12), 3.77 (95% CI: 1.87-7.57) and 5.02 (95% CI: 2.4-10.5) in the noncarriers of allele C, whereas in the carriers the odds ratios were 2.19 (95% CI: 1.42-3.36), 2.03 (95% CI: 1.27-3.23) and 2.92 (95% CI: 1.77-4.82). Thus, there was an independent relationship between IL6R polymorphisms and CRP. Furthermore, IL6R variants may interact with CRP to predict diabetes risk.
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