Deep phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 human knockouts and population based studies

Project Narrative We and others have identified that individuals who carry loss of function (LoF) mutations in the ANGPTL3, ANGPTL4 and ANGPTL8 genes have a natural tendency to have lower plasma triglycerides and as a result lower risk of CHD; hence these three genes in the ANGPTL pathway are being considered as therapeutic targets in CHD. In this application, we will conduct extensive phenotyping studies in the participants who carry LoF mutations in the ANGPTL3, ANGPTL4 and ANGPTL8 genes and matched non-carriers to investigate biology and understand any adverse metabolic effects resulting due to natural deficiency of any of the three genetic products. We will also use data from large population-based studies to help understand the associations of both plasma ANGPTL8 and mutations in the ANGPTL8 gene with a range of cardio-metabolic disorders.