Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality

BACKGROUND: The muscle glycogen synthase gene (GYS1) has been associated with type 2 diabetes (T2D), the metabolic syndrome (MetS), male myocardial infarction and a defective increase in muscle glycogen synthase protein in response to exercise. We addressed the questions whether polymorphism in GYS1 can predict cardiovascular (CV) mortality in a high-risk population, if this risk is influenced by gender or physical activity, and if the association is independent of genetic variation in nearby apolipoprotein E gene (APOE). METHODOLOGY/PRINCIPAL FINDINGS: Polymorphisms in GYS1 (XbaIC>T) and APOE (-219G>T, ε2/ε3/ε4) were genotyped in 4,654 subjects participating in the Botnia T2D-family study and followed for a median of eight years. Mortality analyses were performed using Cox proportional-hazards regression. During the follow-up period, 749 individuals died, 409 due to CV causes. In males the GYS1 XbaI T-allele (hazard ratio (HR) 1.9 [1.2–2.9]), T2D (2.5 [1.7–3.8]), earlier CV events (1.7 [1.2–2.5]), physical inactivity (1.9 [1.2–2.9]) and smoking (1.5 [1.0–2.3]) predicted CV mortality. The GYS1 XbaI T-allele predicted CV mortality particularly in physically active males (HR 1.7 [1.3–2.0]). Association of GYS1 with CV mortality was independent of APOE (219TT/ε4), which by its own exerted an effect on CV mortality risk in females (2.9 [1.9–4.4]). Other independent predictors of CV mortality in females were fasting plasma glucose (1.2 [1.1–1.2]), high body mass index (BMI) (1.0 [1.0–1.1]), hypertension (1.9 [1.2–3.1]), earlier CV events (1.9 [1.3–2.8]) and physical inactivity (1.9 [1.2–2.8]). CONCLUSIONS/SIGNIFICANCE: Polymorphisms in GYS1 and APOE predict CV mortality in T2D families in a gender-specific fashion and independently of each other. Physical exercise seems to unmask the effect associated with the GYS1 polymorphism, rendering carriers of the variant allele less susceptible to the protective effect of exercise on the risk of CV death, which finding could be compatible with a previous demonstration of defective increase in the glycogen synthase protein in carriers of this polymorphism.