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Context: ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored. Objective: To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed ELISA and to identify genetic factors contributing to differences in plasma A8 levels. Design and Setting: Population-based sample of Dallas County. Participants: Individuals in the Dallas Heart Study (DHS-1, n=3,538; DHS-2, n=3,283), including 2,131 individuals with repeated measurements 7-9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). Main Outcome Measure(s): Associations of A8 levels with body-mass index (BMI), plasma levels of glucose, insulin, lipids, hepatic TG and DNA variants identified by exome-wide sequencing. Results: A8 levels varied over a 150-fold range (2.1 - 318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin and TG levels. A variant in A8, R59W, accounted for 17% of the inter-individual variation in A8 levels, but was not associated with the metabolic parameters correlated with plasma A8 concentrations. Conclusions: A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.

Het algemene doel van dit proefschrift betreft de functionele karakterisatie van nieuwe spelers (GPR146) dan wel het ontrafelen van nieuwe rollen van oude spelers (LRP1, ANGPTL3) die betrokken zijn bij dyslipidemie, een gestoorde glucosehuishouding (GALNT2) en/of atherosclerose (LPL, APOA5, LCAT). Er is in dit kader met name aandacht besteed aan moleculaire mechanismes die relevant zijn voor humane ziekebeelden. Hiertoe zijn verschillende benaderingen gebruikt waaronder het uitvoeren van onderzoek in prospectieve humane cohort studies, cellulaire en ook diermodellen.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD.