Gene-gene interactions between HNF4A and KCNJ11 in predicting Type 2 diabetes in women

Recent studies indicate transcription factor hepatocyte nuclear factor 4 alpha (HNF-4 alpha, HNF4A) modulates the transcription of the pancreatic B-cell ATP-sensitive K+ (KATP) channel subunit Kir6.2 gene (KCNJ11). Both HNF4A and KCNJ11 have previously been associated with diabetes risk but little is known whether the variations in these genes interact with each other.

We conducted a prospective, nested case-control study of 714 incident cases of Type 2 diabetes and 1120 control subjects from the Nurses' Health Study.

KCNJ11 E23K was significantly associated with an increased diabetes risk (odds ratio 1.26, 95% CI 1.03-1.53) while HNF4A P2 promoter polymorphisms were associated with a moderately increased risk at borderline significance. By using a logistic regression model, we found significant interactions between HNF4A rs2144908, rs4810424 and rs1884613 and KCNJ11 E23K (P for interaction = 0.017, 0.012 and 0.004, respectively). Carrying the minor alleles of the three HNF4A polymorphisms was associated with significantly greater diabetes risk in women carrying the KCNJ11 allele 23K, but not in those who did not carry this allele. Analyses using the multifactor dimensionality reduction (MDR) method confirmed the gene-gene interaction. We identified that the best interaction model included HNF4A rs2144908 and KCNJ11 E23K. Such a two-locus model showed the maximum cross-validation consistency of 10 out of 10 and a significant prediction accuracy of 54.2% (P = 0.01) on the basis of 1000-fold permutation testing.

Our data indicate that HNF4A P2 promoter polymorphisms may interact with KCNJ11 E23K in predicting Type 2 diabetes in women.