Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c ) levels in non-diabetic subjects: The Long Life Family Study (LLFS)

Abstract Objective Glycated hemoglobin (HbA1c ) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark. Methods A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing. Results Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed ( p < 5e-8). Of 25 suggestive (5e-8 < p < 1e-5) loci, one known ( G6PC2 rs560887, replication p = 5e-5) and one novel ( OR10R3P/SPTA1 − rs12041363, replication p = 1e-17) loci were replicated ( p < 0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P / SPTA1. Conclusions The analysis reconfirmed two known GWAS loci ( GCK , HK1 ) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P / SPTA1 . Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.