Abstract
Serum 1,5-anhydroglucitol (1,5-AG) is an emerging biomarker used to monitor glycemic control in persons with diabetes. We performed whole-exome sequencing, examining the association between rare, coding genetic variants and 1,5-AG among European ancestry (N = 6,589) and African ancestry (N = 2,309) participants without diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Five variants representing 3 independent signals on chromosome 17 in SLC5A10, a glucose transporter not previously known to transport 1,5-AG, were associated with 1,5-AG levels up to 10.38 µg/mL lower per allele (1,5-AG range 3.4–32.8 µg/mL) in the European ancestry sample and validated in the African ancestry sample. Together these variants explained 6% of the variance in 1,5-AG. Two of these variants (rs61741107, p = 8.85E-56; rs148178887, p = 1.13E-36) were rare, nonsynonymous, and predicted to be damaging or deleterious by multiple algorithms. Gene-based SKAT-O analysis supported these results (SLC5A10 p = 5.13E-64 in European ancestry, validated in African ancestry, p = 0.006). Interestingly, these novel variants are not associated with other biomarkers of hyperglycemia or diabetes (p > 0.2). The large effect sizes and protein-altering, multiple independent signals suggest SLC5A10 may code for an important transporter of 1,5-AG in the kidney, with a potential nonglucose-related effect on 1,5-AG, impacting its clinical utility as a diabetes biomarker in this subpopulation.
Highlights
1,5-andhydroglucitol (1,5-AG) is an emerging biomarker of glycemic control in type 2 diabetes. 1,5-AG is a monosaccharide consumed in food and maintained at high, constant levels in the blood under normoglycemic conditions through filtration by the kidney and reabsorption into the blood. 1,5-AG is the 1-deoxy form of glucose, and during hyperglycemic conditions, glucose outcompetes 1,5-AG for reabsorption
In a recent genome-wide association study (GWAS), we identified seven variants at six loci associated with 1,5-AG among persons of European ancestry without diagnosed diabetes[6]
Over half were female, and mean age was 56 to 57 years old. 1,5-AG levels were lower, and fructosamine, glycated albumin, fasting glucose and HbA1c were higher in the African ancestry sample as compared to the European ancestry sample
Summary
1,5-andhydroglucitol (1,5-AG) is an emerging biomarker of glycemic control in type 2 diabetes. 1,5-AG is a monosaccharide consumed in food and maintained at high, constant levels in the blood under normoglycemic conditions through filtration by the kidney and reabsorption into the blood. 1,5-AG is the 1-deoxy form of glucose, and during hyperglycemic conditions (i.e., when glucose exceeds the renal threshold), glucose outcompetes 1,5-AG for reabsorption. 1,5-AG is the 1-deoxy form of glucose, and during hyperglycemic conditions (i.e., when glucose exceeds the renal threshold), glucose outcompetes 1,5-AG for reabsorption This causes 1,5-AG excretion in urine and lower levels in blood concentrations[1]. In a recent genome-wide association study (GWAS), we identified seven variants at six loci associated with 1,5-AG among persons of European ancestry without diagnosed diabetes[6]. Two of these variants were found in a genetic screen of 1,5-AG measured as part of a large non-targeted metabolome panel among Europeans[7]. To investigate the association of rare, putatively damaging variants with 1,5-AG, and to further understand the genetic architecture of this biomarker, a whole-exome sequencing association study of 1,5-AG concentrations was performed in the Atherosclerosis Risk In Communities (ARIC) Study
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