Year: 2018
Type: article
Study design: Observational Study
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.
Institutions: Brigham and Women's Hospital, Harvard University, The University of Texas Health Science Center at Houston, University of North Carolina at Chapel Hill, University of Helsinki, Finnish Institute for Health and Welfare, Oulu University Hospital, University of Oulu, Johns Hopkins University, Johns Hopkins Medicine, Baylor College of Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $7,166
Funders: American Heart Association, Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Alnylam Pharmaceuticals, Foundation for Cardiovascular Research, Celladon Corporation, Yrjö Jahnssonin Säätiö, Ironwood Pharmaceuticals, Incorporated, Zogenix, MyoKardia, Verily Life Sciences, Novo Nordisk, Päivikki ja Sakari Sohlbergin Säätiö, China Scholarship Council, Sydäntutkimussäätiö, National Institutes of Health, Sanofi Pasteur, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1052397333, G1243299691, G1486090915, G1527150935, G1537707606, G1691174148, G173303992, G2178242675, G301743239, G3114902838, G3152385821, G3462919067, G4167445418, G4200864717, Inflammatory Mediators, Cardiovascular Health, and Longevity in Women, G5074086979, Research and Mentoring in the Clinical Epidemiology of Type 2 Diabetes, G567847597, G5978425253, G6195637971, Diabetes and Prediabetes in Older Adults in ARIC, G6540056966, G8225907289, G8558577029, Noninvasive Cardiovascular Imaging Research Training Program, Cardiac microstructure and the immune-inflammatory response to SARS-CoV-2
OpenAlex ID: W2894694027