Abstract

Objective: To examine the associations between common variations in IL6R gene and circulating IL-6 levels and diabetes risk.

Research Design and Methods: we determined ten LD-tagging SNPs (SNP1 to 10) for IL6R gene in a nested case-control study of 672 diabetic and 1,058 healthy European Caucasian women (IL-6 levels were measured in a subgroup of 1,348 women).

Results: In both controls and diabetic patients, polymorphisms within a LD block spanning ∼42 kb were significantly associated with plasma IL-6 levels. A missense variant SNP7 in exon 9 (rs8192284, Asp358Ala) showed the strongest association (P=0.0005 in controls and P=0.004 in cases). The corresponding false-discovery rate (FDR), which accounts for the multiple testing, were 0.008 and 0.02 respectively. We inferred five common haplotypes to capture 94% allele variance of the LD block using SNP5, 7, 8, 9 and 10. As compared with the most common haplotype 12111 (1 codes the common and 2 codes the minor alleles), haplotypes 11211 [difference in log(IL-6)=-0.11, 95% CI -0.23 to -0.01; P=0.01] and 21122 (-0.15, 95% CI -0.27 to -0.03; P=0.01) were associated with significantly lower IL-6 levels (global test, P=0.01). However, IL6R genotypes were not significantly associated with the risk of type 2 diabetes.

Conclusions: IL6R genetic variations, especially SNP7 (rs8192284, Asp358Ala), were significantly associated with plasma IL-6 levels but not with diabetes risk in women. The strong associations between IL6R genetic variability and IL-6 concentrations deserve further investigation.