Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease.

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 (<i>ABCC8</i> 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; <i>P</i> = 1.2 × 10^-11). The variant was associated with increased BMI (+0.062 kg/m²; 95% CI 0.037, 0.086; <i>P</i> = 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; <i>P</i> = 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.