A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans
- Huaixing Li1,
- Wei Gan1,
- Ling Lu1,
- Xiao Dong2,
- Xueyao Han3,
- Cheng Hu4,
- Zhen Yang5,
- Liang Sun6,
- Wei Bao7,8,
- Pengtao Li9,
- Meian He8,10,
- Liangdan Sun11,12,13,
- Yiqin Wang1,
- Jingwen Zhu1,
- Qianqian Ning2,
- Yong Tang3,
- Rong Zhang4,
- Jie Wen5,
- Di Wang7,8,
- Xilin Zhu9,
- Kunquan Guo8,10,
- Xianbo Zuo11,12,13,
- Xiaohui Guo14,
- Handong Yang15,
- Xianghai Zhou3,
- DIAGRAM Consortium*,
- AGEN-T2D Consortium*,
- Xuejun Zhang11,12,13,
- Lu Qi16,
- Ruth J.F. Loos17,18,
- Frank B. Hu16,
- Tangchun Wu8,10,
- Ying Liu9,
- Liegang Liu7,8,
- Ze Yang6,
- Renming Hu5,
- Weiping Jia4,
- Linong Ji3⇓,
- Yixue Li2,19,20⇓ and
- Xu Lin1⇓
- 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China
- 2Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China
- 3Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
- 4Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- 5Institute of Endocrinology and Diabetology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- 6Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China
- 7Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 8Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- 9State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- 10Institute of Occupational Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- 11Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China
- 12Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China
- 13State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China
- 14Peking University First Hospital, Beijing, China
- 15Dongfeng Central Hospital, Dongfeng Motor Corporation and Hubei University of Medicine, Shiyan, Hubei, China
- 16Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
- 17Department of Preventive Medicine, Charles R. Bronfman Institute of Personalized Medicine, Mount Sinai School of Medicine, New York, New York
- 18Department of Preventive Medicine, Child Health and Development Institute, Mount Sinai School of Medicine, New York, New York
- 19Shanghai Center for Bioinformation Technology, Shanghai, China
- 20College of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China
- Corresponding author: Xu Lin, , Yixue Li, , or Linong Ji, .
H.L., W.G., L. Lu, X.D., X.H., C.H., Zh.Y., Liang S., W.B., and P.L. contributed equally to this work.
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein–coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10−9) and RASGRP1 (rs7403531: P = 3.9 × 10−9), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA1c and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.
T.W., Y. Liu, L. Liu, Ze Y., R.H., W.J., L.J., Y. Li, and X.L. jointly directed this work.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0454/-/DC1.
* A complete list of the DIAGRAM Consortium and AGEN-T2D Consortium is provided in the Supplementary Data.
- Received April 12, 2012.
- Accepted June 23, 2012.
- © 2013 by the American Diabetes Association.
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