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.
Bibliographical noteFunding Information:
The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273 and R01HL086694). The work of AK was funded by DFG KO 3598/3-1 and KO 3598/4-1. SL was supported by an institutional training grant from the NIH/NHLBI (T32 HL007024). This work was also supported by NIH/NIDDK grants K24DK106414 and R01DK089174 to Dr. Selvin. Reagents for the 1,5-anhydroglucitol assays were donated by GlycoMark, Inc.