GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

OBJECTIVE-To evaluate the significance of GAD antibodies (GADAs) and family history for type 1 diabetes (FHT1) or type 2 diabetes (FHT2) in nondiabetic subjects. RESEARCH DESIGN AND METHODS-GADAs were analyzed in 4,976 nondiabetic relatives of type 2 diabetic patients or control subjects from Finland. Altogether, 289 (5.9%) were GADA(+)-a total of 253 GADA(+) and 2,511 GADA(-) subjects participated in repeated oral glucose tolerance tests during a median time of 8.1 years. The risk of progression to diabetes was assessed using Cox regression analysis. RESULTS-Subjects within the highest quartile of GADA(+) (GADA(high)(+)) had more often first-degree FHT1 (29.2 vs. 7.9%, P < 0.00001) and GADA(+) type 2 diabetic (21.3 vs. 13.7%, P = 0.002) or nondiabetic (26.4 vs. 13.3%, P = 0.010) relatives than GADA(-) subjects. During the follow-up, the GADA(+) subjects developed diabetes significantly more often than the GADA(-) subjects (36/253 [14.2%] vs. 134/2,511 [5.3%], P < 0.00001). GADA(high)(+) conferred a 4.9-fold increased risk of diabetes (95% CI 2.8-8.5) compared with GADA(-)-seroconversion to positive during the follow-up was associated with 6.5-fold (2.8-15.2) and first-degree FHT1 with 2.2-fold (1.2-4.1) risk of diabetes. Only three subjects developed type 1 diabetes, and others had a non-insulin-dependent phenotype 1 year after diagnosis. GADA(+) and GADA(-) subjects did not clinically differ at baseline, but they were leaner and less insulin resistant after the diagnosis of diabetes. CONCLUSIONS-GADA positivity clusters in families with type 1 diabetes or latent autoimmune diabetes in adults. GADA positivity predicts diabetes independently of family history of diabetes, and this risk was further increased with high GADA concentrations

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, epsilon 2/epsilon 3/epsilon 4) 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/epsilon 4), 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.""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, epsilon 2/epsilon 3/epsilon 4) 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/epsilon 4), 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.""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, epsilon 2/epsilon 3/epsilon 4) 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/epsilon 4), 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."Peer reviewe