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

Abstract

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.

Glomerular Transcriptome Profiles in Focal Glomerulosclerosis: New Genes and Pathways for Steroid Resistance

“…Among the 6 top regulated genes in SRNS: ALDOB (aldolase B), is specifically bound to FBPase in the kidney, and participates in the gluconeogenic pathway [19]. MGAM encodes maltase-glucoamylase, which is an intestinal brush border membrane enzyme involved in carbohydrate digestion [20]. MGAM expresses in the kidney, an important target enzyme for the treatment of type-2 diabetes and also takes part in energy supply [21].…”

Analysis of putative cis-regulatory elements regulating blood pressure variation

“…We analyzed 9,083 individuals of European ancestry with genotypes and QT interval at baseline. The genotyping of these samples on the Affymetrix genome-wide Human SNP Array 6.0, quality control, and imputation to the 1000 Genomes Phase I Integrated Release Version 3 haplotype panel are described elsewhere [69, 70]. We converted IMPUTE2 genotype probabilities to PLINK ‘hard’ calls, setting genotypes with uncertainty greater than 0.25 to missing, and retaining variants with < 10% missing data, a Hardy Weinberg equilibrium test p < 1×10 -6 , and imputation quality score ≥ 0.3, (as for the GERA study).…”

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

“…Furthermore, studies of the renal reabsorption of fructose in rat proximal tubules revealed that this process can be blocked to a large extent by phlorizin and that it is Na +dependent [54]. In addition, recent genome-wide association studies revealed that genetic variations of SGLT5 are associated with impaired 1,5-anhydroglucitol (1,5-AG) blood levels [96]. 1,5-AG is a monosaccharide found in nearly all foods and its blood concentration decreases during times of hyperglycemia and, within a couple of weeks, returns to normal levels in the absence of hyperglycemia.…”