Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4

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• 作者：R. C. W. Ma (1) (2) (3)
  C. Hu (4) (5)
  C. H. Tam (1)
  R. Zhang (4)
  P. Kwan (1)
  T. F. Leung (6)
  G. N. Thomas (7)
  M. J. Go (8)
  K. Hara (10) (9)
  X. Sim (11) (12)
  J. S. K. Ho (1)
  C. Wang (4)
  H. Li (13)
  L. Lu (13)
  Y. Wang (13)
  J. W. Li (14)
  Y. Wang (1)
  V. K. L. Lam (1)
  J. Wang (4)
  W. Yu (4)
  Y. J. Kim (8)
  D. P. Ng (15)
  H. Fujita (9)
  K. Panoutsopoulou (16)
  A. G. Day-Williams (16)
  H. M. Lee (1)
  A. C. W. Ng (1)
  Y-J. Fang (17)
  A. P. S. Kong (1)
  F. Jiang (4)
  X. Ma (4)
  X. Hou (4)
  S. Tang (4)
  J. Lu (4)
  T. Yamauchi (9)
  S. K. W. Tsui (18)
  J. Woo (1)
  P. C. Leung (19)
  X. Zhang (5)
  N. L. S. Tang (20)
  H. Y. Sy (6)
  J. Liu (21)
  T. Y. Wong (22) (23) (24)
  J. Y. Lee (8)
  S. Maeda (25)
  G. Xu (1)
  S. S. Cherny (26)
  T. F. Chan (14)
  M. C. Y. Ng (27)
  K. Xiang (4)
  A. P. Morris (28)
  S. Keildson (28)
  R. Hu (29)
  L. Ji (30)
  X. Lin (13)
  Y. S. Cho (31)
  T. Kadowaki (9)
  E. S. Tai (32) (33)
  E. Zeggini (16)
  M. I. McCarthy (28) (34)
  K. L. Hon (6)
  L. Baum (35)
  B. Tomlinson (1)
  W. Y. So (1)
  Y. Bao (4)
  J. C. N. Chan (1) (2) (3)
  W. Jia (4)
  
• 关键词：Chinese ; Diabetes ; East Asians ; Genetics ; Genome ; wide association study
• 刊名：Diabetologia
• 出版年：2013
• 出版时间：June 2013
• 年：2013
• 卷：56
• 期：6
• 页码：1291-1305
• 全文大小：379KB
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• 作者单位：R. C. W. Ma (1) (2) (3)
  C. Hu (4) (5)
  C. H. Tam (1)
  R. Zhang (4)
  P. Kwan (1)
  T. F. Leung (6)
  G. N. Thomas (7)
  M. J. Go (8)
  K. Hara (10) (9)
  X. Sim (11) (12)
  J. S. K. Ho (1)
  C. Wang (4)
  H. Li (13)
  L. Lu (13)
  Y. Wang (13)
  J. W. Li (14)
  Y. Wang (1)
  V. K. L. Lam (1)
  J. Wang (4)
  W. Yu (4)
  Y. J. Kim (8)
  D. P. Ng (15)
  H. Fujita (9)
  K. Panoutsopoulou (16)
  A. G. Day-Williams (16)
  H. M. Lee (1)
  A. C. W. Ng (1)
  Y-J. Fang (17)
  A. P. S. Kong (1)
  F. Jiang (4)
  X. Ma (4)
  X. Hou (4)
  S. Tang (4)
  J. Lu (4)
  T. Yamauchi (9)
  S. K. W. Tsui (18)
  J. Woo (1)
  P. C. Leung (19)
  X. Zhang (5)
  N. L. S. Tang (20)
  H. Y. Sy (6)
  J. Liu (21)
  T. Y. Wong (22) (23) (24)
  J. Y. Lee (8)
  S. Maeda (25)
  G. Xu (1)
  S. S. Cherny (26)
  T. F. Chan (14)
  M. C. Y. Ng (27)
  K. Xiang (4)
  A. P. Morris (28)
  S. Keildson (28)
  R. Hu (29)
  L. Ji (30)
  X. Lin (13)
  Y. S. Cho (31)
  T. Kadowaki (9)
  E. S. Tai (32) (33)
  E. Zeggini (16)
  M. I. McCarthy (28) (34)
  K. L. Hon (6)
  L. Baum (35)
  B. Tomlinson (1)
  W. Y. So (1)
  Y. Bao (4)
  J. C. N. Chan (1) (2) (3)
  W. Jia (4)
  
  1. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, SAR, People’s Republic of China
  2. Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  3. Li Ka Shing Institute of Life Sciences, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  4. Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of China
  5. Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, People’s Republic of China
  6. Department of Paediatrics, Chinese University of Hong Kong, Hong Kong, People’s Republic of China
  7. Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK
  8. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Gangoe-myeon, Yeonje-ri, Cheongwon-gun, Chungcheongbuk-do, Republic of Korea
  10. Department of Integrated Molecular Science on Metabolic Diseases, University of Tokyo Hospital, Tokyo, Japan
  9. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  11. Centre for Molecular Epidemiology, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Republic of Singapore
  12. Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
  13. Key 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, People’s Republic of China
  14. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  15. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Republic of Singapore
  16. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  17. Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
  18. School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  19. Department of Orthopaedics, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  20. Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  21. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Republic of Singapore
  22. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Republic of Singapore
  23. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
  24. Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia
  25. Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Japan
  26. Department of Psychiatry and State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  27. Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
  28. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  29. Institute of Endocrinology and Diabetology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
  30. Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, People’s Republic of China
  31. Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, Republic of Korea
  32. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
  33. Graduate Medical School, Duke-National University of Singapore, Singapore, Republic of Singapore
  34. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
  35. School of Pharmacy, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China
  
• ISSN：1432-0428

文摘

Aims/hypothesis Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. Methods We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. Results We identified CDKN2A/B and four novel type 2 diabetes association signals with p-lt;-?×-0? from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta--.6?×-0?; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta--.3?×-0?0) and a population of European descent (p--.6?×-0?). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. Conclusions/interpretation Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.