Diabetes Volume 63, July 2014 2551 Peng Chen,1 Fumihiko Takeuchi,2 Jong-Young Lee,3 Huaixing Li,4 Jer-Yuarn Wu,5,6 Jun Liang,7 Jirong Long,8 Yasuharu Tabara,9 Mark O. Goodarzi,10 Mark A. Pereira,11 Young Jin Kim,3 Min Jin Go,3 Daniel O. Stram,12 Eranga Vithana,13–15 Chiea-Chuen Khor,1,14,16,17 Jianjun Liu,1,16 Jiemin Liao,13,14 Xingwang Ye,4 Yiqin Wang,4 Ling Lu,4 Terri L. Young,15,18 Jeannette Lee,1 Ah Chuan Thai,19 Ching-Yu Cheng,1,13,14,20 Rob M. van Dam,1,19 Yechiel Friedlander,21 Chew-Kiat Heng,17 Woon-Puay Koh,1,22 Chien-Hsiun Chen,5,6 Li-Ching Chang,5 Wen-Harn Pan,5 Qibin Qi,23 Masato Isono,2 Wei Zheng,8 Qiuyin Cai,8 Yutang Gao,24 Ken Yamamoto,25 Keizo Ohnaka,26 Ryoichi Takayanagi,27 Yoshikuni Kita,28 Hirotsugu Ueshima,29 Chao A. Hsiung,30 Jinrui Cui,10 Wayne H.-H. Sheu,31–33 Jerome I. Rotter,34 Yii-Der I. Chen,34 Chris Hsu,12 Yukinori Okada,35,36 Michiaki Kubo,37 Atsushi Takahashi,36 Toshihiro Tanaka,35,38 Frank J.A. van Rooij,39 Santhi K. Ganesh,40 Jinyan Huang,41 Tao Huang,41 Jianmin Yuan,42 Joo-Yeon Hwang,43 CHARGE Hematology Working Group, Myron D. Gross,44 Themistocles L. Assimes,45 Tetsuro Miki,46 Xiao-Ou Shu,8 Lu Qi,47,48 Yuan-Tson Chen,5,49 Xu Lin,4 Tin Aung,13 Tien-Yin Wong,13,14 Yik-Ying Teo,1,13,16,50–52 Bong-Jo Kim,3 Norihiro Kato,2 and E-Shyong Tai1,19,22 Multiple Nonglycemic Genomic Loci Are Newly Associated With GENETICS/GENOMES/PROTEOMICS/METABOLOMICS Blood Level of Glycated Hemoglobin in East Asians Diabetes 2014;63:2551–2562 | DOI: 10.2337/db13-1815 Glycated hemoglobin A1c (HbA1c) is used as a measure Glycated hemoglobin A1c (HbA1c) is formed through a of glycemic control and also as a diagnostic criterion for nonenzymatic reaction between glucose and hemoglobin. diabetes. To discover novel loci harboring common var- After formation, HbA1c remains and accumulates primar- iants associated with HbA1c in East Asians, we con- ily in erythrocytes throughout its life span. The blood level ducted a meta-analysis of 13 genome-wide association of HbA1c reflects the average blood glucose level over ;90 studies (GWAS; N = 21,026). We replicated our findings in days. Genome-wide association studies (GWAS) have iden- three additional studies comprising 11,576 individuals of tified variants at multiple loci that are associated with East Asian ancestry. Ten variants showed associations HbA . In several instances, the presence of these variants fi 1c that reached genome-wide signi cance in the discovery is associated with altered glucose homeostasis, e.g., var- TMEM79 data set, of which nine (four novel variants at iants in or near solute carrier family 30 (zinc transporter); P 3 223 HBS1L/MYB 3 215 [ value = 1.3 10 ], [8.5 10 ], member 8 (SLC30A8) (1); transcription factor 7-like MYO9B [9.0 3 10212], and CYBA [1.1 3 1028]aswellas 2(TCF7L2) (2); glucose-6-phosphatase, catalytic, 2 (G6PC2); five variants at loci that had been previously identified glucokinase (GCK); melatonin receptor 1B (MTNR1B)(3); [CDKAL1, G6PC2/ABCB11, GCK, ANK1,andFN3KI]) and CDK5 regulatory subunit associated protein 1-like showed consistent evidence of association in replica- 1(CDKAL1)(4).ThusGWASofHbA may uncover variants tion data sets. These variants explained 1.76% of the 1c that are relevant to the regulation of blood glucose or to the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1,andFN3K) pathogenesis of type 2 diabetes (T2D) and complement showed no association with either blood glucose or GWAS for other glycemic traits. type 2 diabetes. Among individuals with nondiabetic HbA1c is also affected by pathways that are not asso- levels of fasting glucose (<7.0 mmol/L) but elevated ciated with the regulation of blood glucose. For example, HbA (‡6.5%), 36.1% had HbA <6.5% after adjust- in addition to the associations with HbA1c, several variants 1c 1c HFE ment for these six variants. Our East Asian GWAS close to hemochromatosis ( ); transmembrane protease, meta-analysis has identified novel variants associated serine 6 (TMPRSS6);ATPase,classVI,type11A/tubulin, ATP11A TUBGCP3 with HbA1c as well as demonstrated that the effects of g-complex-associated protein 3 ( / ); known variants are largely transferable across ethnic ankyrin 1, erythrocytic (ANK1); spectrin, a, erythrocytic groups. Variants affecting erythrocyte parameters 1(SPTA1); and hexokinase 1 (HK1)alsoshowedsugges- rather than glucose metabolism may be relevant to tive or definitive associations with erythrocyte parameters – the use of HbA1c for diagnosing diabetes in these (5 10). Several of these genes were also known to harbor populations. rare variants that cause hereditary anemias (11–13). These 2552 Genetic Associations With HbA1c in East Asians Diabetes Volume 63, July 2014 raise the possibility that the impact of these variants on (15,16). It is recognized that the glucose and HbA1c criteria HbA1c relates to their effects on erythrocyte half-life. Al- are not completely concordant and that genetic variants ternatively, variants near fructosamine 3 kinase (FN3K) result in a significant reclassification of individuals based may act through their effects on protein deglycation (14). on HbA1c criteria when compared with fasting glucose These effects become particularly relevant now in that criteria (17). HbA1c has been adopted as a diagnosis criterion of diabe- To date, with one exception (4), all GWAS for HbA1c tes, because it exhibits less intraindividual variability than have been conducted in populations of European ances- either fasting glucose or 2-h post challenge glucose after an try. We have already demonstrated that genetic associa- oral glucose tolerance test and does not require fasting tion studies in different ethnic groups offer opportunities 1Saw Swee Hock School of Public Health, National University of Singapore and 31Division of Endocrine and Metabolism, Department of Internal Medicine, National University Health System, Singapore Taichung Veterans General Hospital, Taichung, Taiwan 2National Center for Global Health and Medicine, Tokyo, Japan 32School of Medicine, National Yang-Ming University, Taipei, Taiwan 3Center for Genome Science, National Institute of Health, Osong Health Technol- 33School of Medicine, National Defense Medical Center, Taipei, Taiwan ogy Administration Complex, Chungcheongbuk-do, Republic of Korea 34Institute for Translational Genomics and Biomedical Sciences, Los Angeles 4Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Biomedical Research Institute, Harbor-University of California, Los Angeles Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Medical Center, Torrance, CA Shanghai, China 35Department of Human Genetics and Disease Diversity, Graduate School of 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 6School of Chinese Medicine, China Medical University, Taichung, Taiwan 36Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sci- 7Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of ences, Yokohama, Japan Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, 37Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Jiangsu, China Sciences, Yokohama, Japan 8Vanderbilt Epidemiology Center and Division of Epidemiology, Department of 38Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Medicine, Vanderbilt University School of Medicine, Nashville, TN Sciences, Yokohama, Japan 9Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 39Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Sakyo-ku, Kyoto, Japan the Netherlands 10Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical 40Departments of Internal Medicine and Human Genetics, University of Michigan, Center, Los Angeles, CA Ann Arbor, MI 11Division of Epidemiology and Community Health, School of Public Health, 41Department of Epidemiology, Harvard School of Public Health, Boston, MA University of Minnesota, Minneapolis, MN 42University of Pittsburgh Cancer Institute, Pittsburgh, PA 12Department of Preventive Medicine, Keck School of Medicine, University of 43Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Southern California, Los Angeles, CA Republic of Korea 13Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 44Department of Laboratory Medicine and Pathology, Medical School, University of 14Department of Ophthalmology, National University of Singapore, Singapore Minnesota, Minneapolis, MN 15Neuroscience and Behavioural Disorders (NBD) Program, Duke-National Uni- 45Department of Medicine, Stanford University School of Medicine, versity of Singapore Graduate Medical School, Singapore Stanford, CA 16Genome Institute of Singapore, Agency for Science, Technology and Research, 46Department of Geriatric Medicine, Ehime University Graduate School of Singapore, Singapore Medicine, Toon, Ehime, Japan 17Department of Paediatrics, National University of Singapore, Singapore 47Department of Nutrition, Harvard School of Public Health, Boston, MA 18Duke Eye Center, Duke University Medical Center, Durham, NC 48Channing Division of Network Medicine, Department of Medicine, Brig- 19Department of Medicine, Yong Loo Lin School of Medicine, National University ham and Women’s Hospital and Harvard Medical School, Boston, MA of Singapore, Singapore 49Department of Pediatrics, Duke University