Genome-wide association for HbA1c in Malay identified deletion on SLC4A1 that influences HbA1c independent of glycemia.

CONTEXT 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 non-diabetic Malay individuals. DESIGN AND PARTICIPANTS We conducted a genome-wide association analysis for HbA1c using two Malay studies, the Singapore Malay Eye Study (SiMES, N=1,721 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 four loci at genome-wide significance (P<5x10 -8). Of the four loci, three (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine mapped the HbA1c associations to a 27bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38±0.06% (P=3.5x10 -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 non-glycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to under-diagnosed for diabetes or pre-diabetes when HbA1c is used as the only diagnostic test for diabetes.