Details

Autor(en) / Beteiligte

• TAKEUCHI, Fumihiko
• SERIZAWA, Masakuni
• NAKASHIMA, Naoki
• NAWATA, Hajime
• NAKAMURA, Jiro
• KONO, Suminori
• TAKAYANAGI, Ryoichi
• KATO, Norihiro
• YAMAMOTO, Ken
• FUJISAWA, Tomomi
• NAKASHIMA, Eitaro
• OHNAKA, Keizo
• IKEGAMI, Hiroshi
• SUGIYAMA, Takao
• KATSUYA, Tomohiro
• MIYAGISHI, Makoto

Titel

Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population

Ist Teil von

• Diabetes (New York, N.Y.), 2009-07, Vol.58 (7), p.1690-1699

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population Fumihiko Takeuchi 1 , 2 , Masakuni Serizawa 3 , Ken Yamamoto 4 , Tomomi Fujisawa 5 , Eitaro Nakashima 6 , 7 , Keizo Ohnaka 8 , Hiroshi Ikegami 9 , Takao Sugiyama 10 , Tomohiro Katsuya 5 , Makoto Miyagishi 3 , Naoki Nakashima 11 , Hajime Nawata 12 , Jiro Nakamura 6 , Suminori Kono 13 , Ryoichi Takayanagi 14 and Norihiro Kato 3 1 Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan; 2 Wellcome Trust Sanger Institute, Cambridge, U.K; 3 Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan; 4 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; 5 Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 6 Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; 7 Department of Metabolism and Endocrine Internal Medicine, Chubu Rosai Hospital, Nagoya, Japan; 8 Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 9 Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka, Japan; 10 Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan; 11 Department of Medical Informatics, Kyushu University Hospital, Fukuoka, Japan; 12 Fukuoka Prefectural University, Fukuoka, Tokyo, Japan; 13 Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 14 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Corresponding author: Norihiro Kato, nokato{at}ri.imcj.go.jp . Abstract OBJECTIVE To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population. RESEARCH DESIGN AND METHODS In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs ( P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10 –5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. RESULTS Four loci—1 novel with suggestive evidence ( PEPD on 19q13, P = 1.4 × 10 –5 ) and three previously reported—were identified; the association of CDKAL1 , CDKN2A / CDKN2B, and KCNQ1 were confirmed ( P < 10 –19 ). Moreover, significant associations were replicated in five other candidate loci: TCF7L2 , IGF2BP2 , SLC30A8 , HHEX , and KCNJ11 . There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. CONCLUSIONS The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 28, 2008. Accepted April 7, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.