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Diabetes. 2014 Jul;63(7):2551-62. doi: 10.2337/db13-1815. Epub 2014 Mar 19.

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Author information

1
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
2
National Center for Global Health and Medicine, Tokyo, Japan.
3
Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.
4
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
5
Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanSchool of Chinese Medicine, China Medical University, Taichung, Taiwan.
6
Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu, China.
7
Vanderbilt Epidemiology Center and Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
8
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
9
Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA.
10
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
11
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
12
Singapore Eye Research Institute, Singapore National Eye Centre, SingaporeNeuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore Graduate Medical School, Singapore.
13
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeDepartment of Ophthalmology, National University of Singapore, SingaporeGenome Institute of Singapore, Agency for Science, Technology and Research, Singapore, SingaporeDepartment of Paediatrics, National University of Singapore, Singapore.
14
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeGenome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
15
Singapore Eye Research Institute, Singapore National Eye Centre, SingaporeDepartment of Ophthalmology, National University of Singapore, Singapore.
16
Neuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore Graduate Medical School, SingaporeDuke Eye Center, Duke University Medical Center, Durham, NC.
17
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
18
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeSingapore Eye Research Institute, Singapore National Eye Centre, SingaporeDepartment of Ophthalmology, National University of Singapore, SingaporeCentre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore.
19
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
20
Hebrew University, School of Public Health, Jerusalem, Israel.
21
Department of Paediatrics, National University of Singapore, Singapore.
22
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeDuke-National University of Singapore Graduate Medical School, Singapore.
23
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
24
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
25
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
26
Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
27
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
28
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
29
Department of Health Science, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
30
Department of Health Science, and Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
31
Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
32
Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, TaiwanSchool of Medicine, National Defense Medical Center, Taipei, Taiwan.
33
Institute for Translational Genomics and Biomedical Sciences, Los Angeles Biomedical Research Institute, Harbor-University of California, Los Angeles Medical Center, Torrance, CA.
34
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
35
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
36
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
37
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanLaboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
38
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
39
Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI.
40
Department of Epidemiology, Harvard School of Public Health, Boston, MA.
41
University of Pittsburgh Cancer Institute, Pittsburgh, PA.
42
Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Republic of Korea.
43
Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN.
44
Department of Medicine, Stanford University School of Medicine, Stanford, CA.
45
Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
46
Department of Nutrition, Harvard School of Public Health, Boston, MAChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
47
Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanDepartment of Pediatrics, Duke University Medical Center, Durham, NC.
48
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
49
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeSingapore Eye Research Institute, Singapore National Eye Centre, SingaporeGenome Institute of Singapore, Agency for Science, Technology and Research, Singapore, SingaporeNUS Graduate School for Integrative Science and Engineering, National University of Singapore, SingaporeDepartment of Statistics and Applied Probability, National University of Singapore, Singapore.
50
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, SingaporeDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeDuke-National University of Singapore Graduate Medical School, Singapore e_shyong_tai@nuhs.edu.sg.

Abstract

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

PMID:
24647736
PMCID:
PMC4284402
DOI:
10.2337/db13-1815
[Indexed for MEDLINE]
Free PMC Article

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