Genome-wide association study of 1,5-anhydroglucitol identifies novel genetic loci linked to glucose metabolism

1,5-anhydroglucitol (1,5-AG) is a biomarker of hyperglycemic excursions associated with diabetic complications. Because of its structural similarity to glucose, genetic studies of 1,5-AG can deliver complementary insights into glucose metabolism. We conducted genome-wide association studies of serum 1,5-AG concentrations in 7,550 European ancestry (EA) and 2,030 African American participants (AA) free of diagnosed diabetes from the ARIC Study. Seven loci in/near EFNA1/SLC50A1, MCM6/LCT, SI, MGAM, MGAM2, SLC5A10, and SLC5A1 showed genome-wide significant associations (P < 5 × 10−8) among EA participants, five of which were novel. Six of the seven loci were successfully replicated in 8,790 independent EA individuals, and MCM6/LCT and SLC5A10 were also associated among AA. Most of 1,5-AG-associated index SNPs were not associated with the clinical glycemic markers fasting glucose or the HbA1c, and vice versa. Only the index variant in SLC5A1 showed a significant association with fasting glucose in the expected opposing direction. Products of genes in all 1,5-AG-associated loci have known roles in carbohydrate digestion and enteral or renal glucose transport, suggesting that genetic variants associated with 1,5-AG influence its concentration via effects on glucose metabolism and handling.