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OBJECTIVE-The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes 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 type 2 diabetic patients and 402 control subjects 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 type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rsl0811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298-2.263]). 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 type 2 diabetic patients after adjustment for other confounding factors.
CONCLUSIONS-Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background. Diabetes 58:493-498, 2009
A great number of studies in various populations have suggested an association between several single-nucleotide polymorphisms (SNPs) and type 2 diabetes. For example, transcription factor 7-like 2 (TCF7L2) is a highly reliable predisposing gene for type 2 diabetes (1-3). In addition, recent genomewide association studies (GWASs) have provided new susceptible loci for type 2 diabetes (4-10). A GWAS in French subjects, for example, identified rs 13266634, a nonsynonymous SNP (R325W) on the solute carrier family 30 member 8 (SLC30A8) gene, as a polymorphism involved in type 2 diabetes susceptibility (4). The study also reported an association between type 2 diabetes and rsllll875, as well as rs7923837, located in the hematopoietically expressed homeobox gene (HHEX). These associations were replicated in three independent GWASs in various populations (5-7).
Additional susceptible SNPs were independently identified in the insulin-like growth factor 2 mRNA-binding protein 2 gene (IGF2BP2, rs4402960, and rs 1470569)...