Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening
- Yasuharu Tabara1,
- Haruhiko Osawa2,
- Ryuichi Kawamoto3,
- Hiroshi Onuma2,
- Ikki Shimizu4,
- Tetsuro Miki5,
- Katsuhiko Kohara5 and
- Hideichi Makino2
- 1Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
- 2Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
- 3Department of Internal Medicine, Seiyo City Nomura Hospital, Seiyo City, Ehime, Japan
- 4Department of Internal Medicine, Ehime Prefectural Hospital, Toon City, Ehime, Japan
- 5Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
- Corresponding author: Yasuharu Tabara, tabara{at}m.ehime-u.ac.jp, or Haruhiko Osawa, harosawa{at}m.ehime-u.ac.jp
Abstract
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 (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.
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.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 25 November 2008.
Y.T. and H.O. contributed equally to this work.
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- Accepted November 17, 2008.
- Received December 18, 2007.
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