Tabara Yasuharu, Osawa Haruhiko, Kawamoto Ryuichi, Onuma Hiroshi, Shimizu Ikki, Miki Tetsuro, Kohara Katsuhiko, Makino Hideichi
Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan.
Diabetes. 2009 Feb;58(2):493-8. doi: 10.2337/db07-1785. Epub 2008 Nov 25.
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.
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).
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 (rs10811661), 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.
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.
本研究旨在证实全基因组关联研究中的候选基因与日本糖尿病患者及社区普通人群2型糖尿病之间可能存在的关联。对来自TCF7L2、CDKAL1、HHEX、IGF2BP2、CDKN2A/B、SLC30A8和KCNJ11基因的11个先前报道的单核苷酸多态性（SNP）进行了分析。
对506例2型糖尿病患者和402例对照者的候选SNP进行基因分型，并与之前六项针对日本患者的关联研究进行荟萃分析。在一个普通人群样本（n = 1963，年龄61±13岁）中研究与空腹血浆胰岛素水平的关联。
在我们的病例对照研究对象中，TCF7L2（rs12255372）、CDKAL1（rs7756992、rs7754840）、HHEX（rs7923837）、IGF2BP2（rs4402960和rs1470579）、CDKN2A/B（rs10811661）和SLC30A8（rs13266634）与2型糖尿病易感性相关得到重复验证。除这些多态性外，荟萃分析证实2型糖尿病易感性与KCNJ11 rs5219、TCF7L2 rs7903146和HHEX rs1111875相关。TCF7L2 rs12255372多态性对2型糖尿病的优势比（OR）最高（OR 1.714 [1.298 - 2.263]）。其他多态性的优势比范围为1.13至1.41。在调整其他混杂因素后，CDKAL1 rs7756992的风险等位基因与2型糖尿病患者较低的胰岛素水平显著相关。
在日本人中证实了七个候选基因的2型糖尿病易感性。2型糖尿病易感位点的保守性与种族背景无关。
