Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia.

Jin-Fang Chai, Shih-Ling Kao, Chaolong Wang, Victor Jun-Yu Lim, Ing Wei Khor, Jinzhuang Dou, Anna I Podgornaia, Sonia Chothani, Ching-Yu Cheng, Charumathi Sabanayagam, Tien-Yin Wong, Rob M van Dam, Jianjun Liu, Dermot F Reilly, Andrew D Paterson, Xueling Sim

Journal: The Journal of clinical endocrinology and metabolism 2021;105(12):dgaa658

PMID: 32936915

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Abstract

CONTEXT

Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.

OBJECTIVE

To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.

DESIGN AND PARTICIPANTS

We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.

RESULTS

Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level.

CONCLUSION

We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

Address: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.; Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Merck Research Laboratories, Kenilworth, New Jersey.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.; Department of Nutrition, Harvard T.H Chan School of Public Health, Boston, Massachusetts.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Merck Research Laboratories, Kenilworth, New Jersey.; Janssen Pharmaceuticals Inc, Titusville, New Jersey.; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Canada.

DOI: 10.1210/clinem/dgaa658

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MeSH Terms: Adolescent, Adult, Aged, Anion Exchange Protein 1, Erythrocyte, Asian People, Blood Glucose, Case-Control Studies, Cohort Studies, Cross-Sectional Studies, Elliptocytosis, Hereditary, Ethnicity, Female, Gene Deletion, Genome-Wide Association Study, Glycated Hemoglobin, Humans, Malaysia, Male, Middle Aged, Polymorphism, Genetic, Singapore, Young Adult