Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk.

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 (ß-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 (ß = -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 (ß = -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.