title: Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.
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.
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D001786:Blood Glucose / Q000235:genetics*; D015331:Cohort Studies; D005202:Asia, Eastern / Q000453:epidemiology; D005260:Female; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human