Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

Sara B Seidelmann, Elena Feofanova, Bing Yu, Nora Franceschini, Brian Claggett, Mikko Kuokkanen, Hannu Puolijoki, Tapani Ebeling, Markus Perola, Veikko Salomaa, Amil Shah, Josef Coresh, Elizabeth Selvin, Calum A MacRae, Susan Cheng, Eric Boerwinkle, Scott D Solomon, Sara B Seidelmann, Elena Feofanova, Bing Yu, Nora Franceschini, Brian Claggett, Mikko Kuokkanen, Hannu Puolijoki, Tapani Ebeling, Markus Perola, Veikko Salomaa, Amil Shah, Josef Coresh, Elizabeth Selvin, Calum A MacRae, Susan Cheng, Eric Boerwinkle, Scott D Solomon

Abstract

Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized.

Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences.

Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed.

Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90).

Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

Keywords: Mendelian randomization; SGLT1; glucose tolerance.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

CENTRAL ILLUSTRATION. Phenotype of Participants in the…
CENTRAL ILLUSTRATION. Phenotype of Participants in the ARIC Study Cohort According to SGLT1 Asn51Ser/Ala411Thr/His615Gln Haplotype Carrier Status
Whole exome sequencing of Sgltl was performed in ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. Among 5,687 European-American subjects (mean age 54 ± 6 years), those who carried a haplotype of 3 missense mutations (Asn51Ser, Ala411Thr, and His615Gln) had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers. The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects and an external European-Finnish population sample of 6,784. Using a Mendelian randomization approach in the index cohort, we estimated the 25-year effect of a 20 mg/dl reduction in 2-h glucose via sodium/glucose cotransporter-1 (SGLT1) inhibition on prevalent obesity, incident diabetes, heart failure, and death. DILGOM = Dietary, Lifestyle and Genetic Predictors of Obesity and Metabolic Syndrome.

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Source: PubMed

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