The -174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, Lung and Blood Institute's Framingham Heart Study

Aims/hypothesis: We evaluated the -174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis.Methods: We tested for associations between the -174 IL-6 G/C promoter polymorphism and fasting plasma glucose (FPG) and type 2 diabetes in a sample of 1,428 individuals from the largest 182 families in the National Heart, Lung and Blood Institute's Framingham Heart Study population. Results: A significant association was found with FPG (p=0.01) and log (FPG) (p=0.005) using a modified family-based transmission disequilibrium test, the family-based association test (FBAT). The association between IL-6 genotype and FPG (p=0.035) and log (FPG) (p=0.03) was also found in the subset of families that were informative in FBAT using a mixed-effects regression model and strengthened after adjustment for potential confounders (p=0.008 for log [FPG]). The mean glucose level estimated from models with log (FPG) as the dependent variable for the GG genotype in the informative families was significantly lower (5.20 +/- 0.06 mmol/l) than for the GC (5.41 +/- 0.06 mmol/l) and CC (5.38 +/- 0.06 mmol/l) genotypes (p=0.03 for contrast between GG and GC genotypes). In the subset of informative families, the risk of type 2 diabetes associated with the GG genotype was lower relative to the GC and CC genotypes combined (potential confounder-adjusted, mixed-effects odds ratio 0.35, 95% CI 0.14-0.88, p=0.026, unaffected n=391, affected n=32). Conclusion/Interpretaion: These results are consistent with a protective role for the -174 IL-6 G allele against type 2 diabetes and warrant further analysis of this polymorphism.