Conserved Haplotype in SGLT1 and Risk for Dietary Hyperglycemia
Authors: SEIDELMANN SARA B. , FEOFANOVA ELENA , YU BING , FRANCESCHINI NORA , CLAGGETT BRIAN , KUOKKANEN MIKKO , EBELING TAPANI M. , PEROLA MARKUS , SALOMAA VEIKKO , SHAH AMIL , CORESH JOSEF , SELVIN ELIZABETH , MACRAE CALUM A. , CHENG SUSAN , BOERWINKLE ERIC , SOLOMON SCOTT 
Published: June 2018

Background: Loss of function mutations in SGLT1 lead to a rare, severe malabsorption disorder and neonatal death if untreated. The clinical consequence of SGLT1 variation in the general population is unknown.
Methods: Exome sequencing was performed in participants from 4 U.S. communities in the ARIC Study. Association of nonsynonymous substitutions (NS) in SGLT1 with impaired glucose tolerance (IGT) and other cardiometabolic outcomes were assessed.
Results: Among 5687 European Americans (mean age 54±6), those with at least two NS in SGLT1 had lower odds of IGT and obesity than non-carriers determined by a relatively common (6.7%) haplotype of 3 missense mutations: Asn51Ser, Ala411Thr, and His615Gln [IGT, OR=0.71 (0.59-0.86); obesity, OR=0.79 (0.66-0.96)]. Replication in African Americans n=2791 confirmed the association of reduced IGT [0.39 (0.17-0.91)] and obesity [0.60 (0.37-0.98)] in haplotype carriers. In combined ARIC samples, haplotype carriers had reduced DM and death or heart failure [HR=0.81 (0.69-0.94) and 0.80 (0.70-0.91)]. Association of the haplotype with lower IGT, obesity, and death persisted in meta-analysis with an external Finnish sample (n=27,294).
Conclusions: Missense variants in SGLT1 protect from diet induced hyperglycemia and may protect from obesity and additional disease outcomes in multiple populations, providing support for therapies that target SGLT1 to prevent and treat metabolic conditions.
OGTT and obesity according to the Asn51Ser/Ala411Thr/His615Gln haplotype in SGLT1Oral Glucose Tolerance TestFasting Glucose Value (mg/dL; beta-coefficients)2-hour Glucose Value (mg/dL; beta-coefficients)Impaired Glucose Tolerance OR (95%CI)Prevalent Obesity OR (95%CI)ARIC European-Americans-2.7 (-5.1, -0.3)-8.0 (-12.7, -3.3)0.71 (0.59, 0.86)0.79 (0.66, 0.96)ARIC African-Americans-4.3 (-19.7, 11.1)-16.3 (-36.6, 4.1)0.39 (0.17, 0.91)0.60 (0.37, 0.98)ARIC Combined-5.9 (-9.1, -2.8)-8.1 (-13.0, -3.2)0.72 (0.59, 0.87)0.66 (0.55, 0.79)P-value‡2.2 x 10-41.2 x 10-38.3 x 10-41.3 x 10-5FINRISK/DILGOM-0.3 (-1.5, 1.1)-3.2 (-4.8, -1.6)0.81 (0.68, 0.98)0.89 (0.71, 1.12)Meta-Analysis-1.1 (-2.3, 0.1)-4.7 (-7.3, -2.0)0.77 (0.67, 0.88)0.74 (0.64, 0.85)P-value‡0.086.5 x 10-48.9 x 10-53.3x10-5

Disclosure
S.B. Seidelmann: None. E. Feofanova: None. B. Yu: None. N. Franceschini: None. B. Claggett: Consultant; Self; Boehringer Ingelheim GmbH. M. Kuokkanen: None. T.M. Ebeling: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Merck Sharp & Dohme Corp.. M. Perola: None. V. Salomaa: Other Relationship; Self; Novo Nordisk Inc.. A. Shah: None. J. Coresh: None. E. Selvin: None. C.A. MacRae: Research Support; Self; Verily Life Sciences LLC., AstraZeneca, American Heart Association, National Institutes of Health, Merck & Co., Inc., Sanofi-Aventis. S. Cheng: None. E. Boerwinkle: None. S. Solomon: Consultant; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Janssen Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Bayer AG, Amgen Inc., Theracos, Inc..