期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 72, 期 15, 页码 1763-1773出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2018.07.061
关键词
glucose tolerance; Mendelian randomization; SGLT1
资金
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820110000 9C, HHSN268201100010C, HHSN268201100011C, HHSN26820 1100012C]
- National Institutes of Health (NIH) [2T32HL094301-06]
- Finnish Foundation for Cardiovascular Research
- EU FP7 [313010, 305280, HZ2020 633589]
- Finnish Academy [269517]
- Yrjo Jahnsson Foundation
- Paivikki and Sakari Sohlberg Foundation
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases [K24DK106414, R01DK089174]
- NIH [R01HL131532, R01HL134168]
- Novartis
- Bellerophon
- American Heart Association
- Verily
- AstraZeneca Merck
- Sanofi
- Alnylam
- Amgen
- AstraZeneca
- Bristol-Myers Squibb
- Celladon
- Gilead
- GlaxoSmithKline
- Ionis
- Lone Star Heart
- Mesoblast
- MyoKardia
- NIH/National Heart, Lung, and Blood Institute
- Sanofi Pasteur
- Theracos
- Novo Nordisk
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL131532, R01HL134168, T32HL094301] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K24DK106414, R01DK089174] Funding Source: NIH RePORTER
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 goat 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 cardiometabotic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 +/- 6 years; 47% mate), 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 (beta-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 (beta = -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 (beta = -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. (C) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.
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