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Objective: We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data., Research Design and Methods: We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT)., Results: Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P = 4 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 10(-4)), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P = 4 x 10(-4)). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9-8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants., Conclusions: If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic beta-cell function in the pathogenesis of type 2 diabetes.

Background--There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. Methods and Results--The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, highdensity lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from P=3.3×10-69 to P=1.1×10-123). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (Pinteraction=9.8×10-5 and 2.0×10-5, respectively, in combined analysis). Conclusions--Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically atrisk individuals may benefit more from targeted interventions aiming at obesity prevention. [ABSTRACT FROM AUTHOR]

Objective: Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. Research Design and Methods: By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twentyone tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS). Results: 273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. Conclusions: Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS. [ABSTRACT FROM AUTHOR]