Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening

Abstract

Objective. The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes mellitus (T2DM) in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8 and KCNJ11 genes were analyzed.

Research Design and Methods. Candidate SNPs were genotyped in 506 T2DM patients and 402 controls, and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample (n=1,963, 61±13 years).

Results. In our case-control subjects, susceptibility to T2DM was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661) and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of T2DM susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146 and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio for T2DM (OR; OR=1.714 (1.298 to 2.263)). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in T2DM patients after adjustment for other confounding factors.

Conclusions. T2DM susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for T2DM was independent of ethnic background.