Interleukin-6 Receptor Gene, Plasma C-Reactive Protein, and Diabetes Risk in Women

OBJECTIVE—Recent genome-wide association studies (GWASs) related common variants in the interleukin-6 (Il-6) receptor (IL6R) gene to plasma C-reactive protein (CRP) concentrations. Because IL6R variants were previously associated with IL-6 levels, we tested whether the associations with CRP were independent of IL-6 and the interactions between IL6R variants and CRP in relation to diabetes risk. RESEARCH DESIGN AND METHODS—Plasma CRP and IL-6 levels and 10 IL6R polymorphisms were determined in a nested case-control study of 633 diabetic and 692 healthy Caucasian women. RESULTS—In both nondiabetic and diabetic women, IL6R polymorphisms were associated with plasma CRP levels, independent of IL-6 concentration. After adjustment of IL-6 levels, CRP concentrations in the genotype AA, AC, and CC of the GWAS polymorphism rs8192284 were 0.32, 0.26, and 0.24 pg/ml, respectively, among nondiabetic women (P for trend = 0.003; false discovery rate [FDR] = 0.01) and 0.63, 0.48, and 0.43 pg/ml among diabetic women (P for trend <0.0001; FDR = 0.0001). Haplotypes inferred from polymorphisms within a linkage disequilibrium block including rs8192284 were also significantly associated with CRP levels (P = 0.0002). In an exploratory analysis, rs8192284 showed significant interactions with CRP levels in relation to diabetes risk (P for interaction = 0.026). The odds ratios across increasing quartiles of CRP were 2.19 (95% CI 1.42–3.36), 2.03 (1.27–3.23), and 2.92 (1.77–4.82) in the carriers of allele-C and 2.21 (1.18–4.12), 3.77 (1.87–7.57), and 5.02 (2.4–10.5) in the noncarriers. CONCLUSIONS—IL6R variants were significantly associated with plasma CRP, independent of IL-6 levels. IL6R variants may interact with CRP in predicting diabetes risk.