1. Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease
- Author
-
Amit Khera, Connor A. Emdin, Derek Klarin, Jose C. Florez, Pradeep Natarajan, and Sekar Kathiresan
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Databases, Factual ,Pharmacogenomic Variants ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Coronary Disease ,Genome-wide association study ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Sulfonylurea Receptors ,Lower risk ,Gastroenterology ,ABCC8 ,Body Mass Index ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Insulin ,Medicine ,Genetic Predisposition to Disease ,biology ,Waist-Hip Ratio ,business.industry ,Body Weight ,Genetic Variation ,Odds ratio ,medicine.disease ,Sulfonylurea ,3. Good health ,Sulfonylurea Compounds ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,biology.protein ,Sulfonylurea receptor ,business ,Genome-Wide Association Study - Abstract
Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacological therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120,286 participants in the UK Biobank and summary association results from four large-scale genome-wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes, and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (odds ratio [OR] 0.93; 95% CI 0.91, 0.95; P = 1.2 × 10−11). The variant was associated with increased BMI (+0.062 kg/m2; 95% CI 0.037, 0.086; P = 8.1 × 10−7) but lower waist-to-hip ratio adjusted for BMI, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98; 95% CI 0.96, 0.99; P = 5.9 × 10−4). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.
- Published
- 2017