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.


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.
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. nhlqi@channing.harvard.edu
Lu
L
Qi
Nader
N
Rifai
Frank B
FB
Hu
D002097:C-Reactive Protein / Q000032:analysis*; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000097:blood* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D012307:Risk Factors
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein