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.


Figure S2. Manhattan plot of the results of the GWAS of 1,5-anhydroglucitol in
African American participants from the ARIC study. The y-axis represents thelog 10 (association p-values) and the x-axis the genomic position (GRCh build37). The red dotted line indicates the genome-wide significance threshold (P<5x10 -8 ), the blue dotted line the suggestive significance threshold (P<1x10 -6 ).

Gene Name
Gene Description EFNA1 EFNA1 encodes a member of the ephrin (EPH) family. Diseases associated with EFNA1 include arteriovenous malformation. Previous GWAS studies have found variants in EFNA1 are associated with liver enzyme levels, prostate cancer, and obesity related traits.

MCM6
MCM6 encodes one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. Previous studies have found variants in MCM6 are associated with lactate intolerant in early adulthood.

SI
SI encodes a sucrose-isomaltase enzyme that is expressed in the intestinal brush border. Mutations in this gene are the cause of congenital sucrose-isomaltase deficiency.

SLC50A1
SLC50A1 is a protein coding gene. GO annotations related to this gene include glucoside transmembrane transporter activity.

MGAM
MGAM encodes maltase-glucoamylase that plays a role in the final steps of digestion of starch. Previous GWAS studies found variants in this gene are associated with blood metabolite levels, bitter taste response/reception, and anorexia nervosa.

MGAM2
MGAM2 is an important paralog of MGAM. It has been associated with carbohydrate binding and glucan 1,4-alphaglucosidase activity.

SLC5A1
SLC5A1 encodes a integral membrane protein that is the primary mediator of dietary glucose and galactose uptake from the intestinal lumen. Mutations in this gene have been associated with glucose-galactose malabsorption.

SLC5A10
This gene is a member of the sodium/glucose transporter family. The protein encoded by this gene has the highest affinity for mannose and has been reported to be most highly expressed in the kidney. This protein may function as a kidney-specific, sodium-dependent mannose and fructose co-transporter. Alternative splicing results in multiple transcript variants that encode different protein isoforms.

LCT
LCT encodes glycosyl hydrolase 1 familty of proteins. Mutations in this gene are associated with congenital lactase deficiency. Polymorphisms in this gene are associated with lactase persistence.  (1) -0.0017 (0.0068) 0.80 a The association result with fasting glucose was extracted from the published MAGIC Consortium GWAS result 1 . b The gene closest to the variant and other candidate genes are listed (index gene). c R 2 information was calculated from the 1000 Genomes Project Phase 3 in European (EUR) population. d rs13229622 is an independent SNP with genome-wide significant association with 1,5-AG found through conditional analysis. A1 is the effect allele, i.e. the allele for which effect estimates are provided. Abbreviations: Chr = chromosome; AF = effect allele frequency; SE = standard error; SNV = single nucleotide variation; Expl Var = proportion of 1,5-AG variance explained