University of Oulu

Seidelmann, S., Feofanova, E., Yu, B., Franceschini, N., Claggett, B., Kuokkanen, M., Puolijoki, H., Ebeling, T., Perola, M., Salomaa, V., Shah, A., Coresh, J., Selvin, E., MacRae, C., Cheng, S., Boerwinkle, E., Solomon, S. (2018) Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. Journal of the American College of Cardiology, 72 (15), 1763-1773. doi:10.1016/j.jacc.2018.07.061

Genetic variants in SGLT1, glucose tolerance, and cardiometabolic risk

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Author: Seidelmann, Sara B.1,2; Feofanova, Elena3; Yu, Bing3;
Organizations: 1Cardiovascular Division, Harvard Medical School and Brigham and Women’s Hospital
2Division of Cardiovascular Imaging, Harvard Medical School and Brigham and Women’s Hospital
3Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health
4Department of Epidemiology, UNC Gilling Global School of Public Health
5National Institute for Health and Welfare, Helsinki
6University of Helsinki, Diabetes and Obesity Research Program
7South Ostrobothnia Hospital District, Seinäjoki
8Department of Medicine, Oulu University Hospital and University of Oulu
9Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and Welch Center for Prevention, Epidemiology, and Clinical Research and Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine
10Human Genome Sequencing Center, Baylor College of Medicine
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018102638816
Language: English
Published: Elsevier, 2018
Publish Date: 2018-10-26
Description:

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.

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Series: JACC. Journal of the American College of Cardiology
ISSN: 0735-1097
ISSN-E: 1558-3597
ISSN-L: 0735-1097
Volume: 72
Issue: 15
Pages: 1763 - 1773
DOI: 10.1016/j.jacc.2018.07.061
OADOI: https://oadoi.org/10.1016/j.jacc.2018.07.061
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 Internal medicine
Subjects:
Funding: The ARIC study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820110000 9C, HHSN268201100010C, HHSN268201100011C, and HHSN26820 1100012C). Dr. Seidelmann was supported by National Institutes of Health (NIH) grant number 2T32HL094301-06. Dr. Salomaa was supported by the Finnish Foundation for Cardiovascular Research. Dr. Perola has received support from the EU FP7 under grant agreements nr. 313010 (BBMRI-LPC), nr. 305280, and HZ2020 633589 (Ageing with Elegans); The Finnish Academy grant no. 269517; and from the Yrjö Jahnsson Foundation. Dr. Kuokkanen was supported by the Päivikki and Sakari Sohlberg Foundation. Dr. Selvin was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants K24DK106414 and R01DK089174. Dr. Cheng was supported by NIH grants R01HL131532 and R01HL134168. There was no direct role of any funder in the design, collection, analysis, or interpretation of the data, nor in the preparation, review, or approval of the manuscript. Dr. Claggett has consulted for Corvia, Gilead, AOBiome, and Boehringer Ingelheim. Dr. Shah has received research funding from Novartis and Bellerophon; and has consulted for Philips Ultrasound, Bellerophon, and GlaxoSmithKline. Dr. Cheng has consulted for Novartis and Zogenix. Dr. MacRae has received research funding from the American Heart Association, Verily, AstraZeneca Merck, Sanofi, and Novartis. Dr. Boerwinkle has served as a scientific officer for Codified Genomics, LLC. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, Theracos; and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. These relationships did not fund the current study. Dr. Salomaa has participated in a conference trip sponsored by Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Academy of Finland Grant Number: 269517
Detailed Information: 269517 (Academy of Finland Funding decision)
Copyright information: © 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  https://creativecommons.org/licenses/by-nc-nd/4.0/