Plasma Triglyceride Level Quantitative Trait Locus

A number sign (#) is used with this entry because of evidence that plasma triglyceride levels are affected by variation in the ANGPTL4 gene (605910) on chromosome 19p13.

Molecular Genetics

Romeo et al. (2009) found an association between lower plasma triglyceride levels and higher HDL with a glu40-to-lys variant (E40K; 605910.0001) in the ANGPTL4 gene, with an allelic frequency of 3% in European Americans. Romeo et al. (2009) then resequenced the coding regions of the genes encoding ANGPTL3 (604774), ANGPTL4, ANGPTL5 (607666), and ANGPTL6 (609336) and identified multiple rare nonsynonymous sequence variations that were associated with low plasma triglyceride levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL4 that were associated with low plasma triglyceride levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL to inhibit lipoprotein lipase (LPL). A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma triglyceride in the lowest quartile had a rare loss-of-function mutation in ANGPTL3, ANGPTL4, or ANGPTL5. However, ANGPTL6 did not play a role in triglyceride metabolism. Romeo et al. (2009) also found missense variants in ANGPTL4 associated with the highest quartile of triglyceride levels in the Dallas Heart Study.

Dewey et al. (2016) sequenced the exons of ANGPTL4 in DNA samples from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. Triglyceride levels were 13% lower and HDL cholesterol levels were 7% higher among carriers of the E40K variant than noncarriers. Carriers of E40K were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; p = 0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. In addition, carriers of other inactivating mutations in ANGPTL4 also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than noncarriers.

The Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators (2016) examined sequence data for the 7 protein-coding exons of ANGPTL4 in 6,924 patients with early-onset myocardial infarction and 6,834 controls, and detected 10 variants predicted to result in loss of gene function, carried by 28 heterozygous individuals. Carriers of loss-of-function alleles had significantly lower levels of triglycerides than did noncarriers (mean, 35% lower; p = 0.003), with no significant differences in LDL or HDL cholesterol levels. In addition, there was a lower risk of coronary artery disease among carriers of loss-of-function alleles (odds ratio for disease, 0.47; p = 0.04).

Animal Model

In mice with a genetic predisposition to hypertriglyceridemia as well as cynomolgus monkeys on a high-fat diet, Dewey et al. (2016) performed monoclonal antibody inhibition of Angptl4 and observed reduced triglyceride levels.