Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study

Stephanie J. Loomis, Anna Köttgen, Man Li, Adrienne Tin, Josef Coresh, Eric Boerwinkle, Richard Gibbs, Donna Muzny, Jim Pankow, Elizabeth Selvin, Priya Duggal

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5941
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Atherosclerosis
Serum
Biomarkers
Exome
Chromosomes, Human, Pair 17
Facilitative Glucose Transport Proteins
1,5-anhydroglucitol
Hyperglycemia
Alleles
Kidney
Genes
Proteins

PubMed: MeSH publication types

  • Journal Article

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Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study. / Loomis, Stephanie J.; Köttgen, Anna; Li, Man; Tin, Adrienne; Coresh, Josef; Boerwinkle, Eric; Gibbs, Richard; Muzny, Donna; Pankow, Jim; Selvin, Elizabeth; Duggal, Priya.

In: Scientific reports, Vol. 9, No. 1, 5941, 01.12.2019.

Research output: Contribution to journalArticle

Loomis, SJ, Köttgen, A, Li, M, Tin, A, Coresh, J, Boerwinkle, E, Gibbs, R, Muzny, D, Pankow, J, Selvin, E & Duggal, P 2019, 'Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study', Scientific reports, vol. 9, no. 1, 5941. https://doi.org/10.1038/s41598-019-42202-0
Loomis, Stephanie J. ; Köttgen, Anna ; Li, Man ; Tin, Adrienne ; Coresh, Josef ; Boerwinkle, Eric ; Gibbs, Richard ; Muzny, Donna ; Pankow, Jim ; Selvin, Elizabeth ; Duggal, Priya. / Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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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.",
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AU - Köttgen, Anna

AU - Li, Man

AU - Tin, Adrienne

AU - Coresh, Josef

AU - Boerwinkle, Eric

AU - Gibbs, Richard

AU - Muzny, Donna

AU - Pankow, Jim

AU - Selvin, Elizabeth

AU - Duggal, Priya

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N2 - 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.

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