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Inactivating mutation confers lower triglycerides, protection from CAD
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People who carry inactivating mutations of the ANGPTL4 gene have lower levels of triglycerides and are at lower risk for CAD compared with the general population, according to two genetic studies published in The New England Journal of Medicine.
The two studies, one funded primarily by the NIH and one funded by Regeneron, came to the same conclusions after comparing people with the mutations against the general population and could prompt research into a new therapeutic pathway.
NIH study
In the study primarily funded by the NIH, investigators from the Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia conducted DNA genotyping on 72,868 patients with CAD and 120,770 controls without CAD.
They tested 54,003 coding-sequence variants for 13,715 genes and analyzed the effects of loss-of-function mutations of certain genes.
They confirmed previously observed associations between CAD and rare variants in LPA and PCSK9, and found associations between CAD and a rare variant in SVEP1 (p.D2702G; minor-allele frequency, 3.6%; OR for CAD = 1.14; P = 4.2 x 10-10) and between reduced risk for CAD and a rare variant in ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; OR for CAD = 0.86; P = 4 x 10-8).
When the researchers sequenced ANGPTL4, which encodes angiopoietin-like 4, they found that the control group was more likely to have carriers of loss-of-function mutations (19 of 6,834) than those with MI (nine of 6,924; OR = 0.47; P = .04).
In addition, carriers of ANGPTL4 loss-of-function mutations had 35% lower triglyceride levels than noncarriers (P = .003), they found.
Because angiopoietin-like 4 inhibits lipoprotein lipase, the researchers then searched for mutations in LPL associated with CAD risk. They found two: one that confers increased risk for CAD (p.D36N; minor-allele frequency, 1.9%; OR = 1.13; P = 2 x 10-4) and one that confers reduced risk for CAD (p.S447*; minor-allele frequency, 9.9%; OR = 0.94; P = 2.5 x 10-7).
“Our results highlight the LPL pathway as a significant contributor to the risk [for CAD] and support speculation that therapeutic modulation of this pathway might be protective against [CAD],” the researchers wrote.
Regeneron study
In the study funded by Regeneron, researchers sequenced exons of ANGPTL4, which they targeted because the gene inhibits lipoprotein lipase, which is associated with reduction of circulating triglycerides, from samples of 42,930 participants of the DiscovEHR genetics study.
Frederick E. Dewey, MD, from the Regeneron Genetics Center, and colleagues tested for the association between lipid levels and the E40K variant, which had been shown to be linked to reduced plasma lipid levels, and other inactivating mutations.
Then they tested for any association between CAD and the E40K variant and other inactivating mutations in 10,552 people with CAD and 29,223 controls without CAD. They also tested whether a human monoclonal antibody against ANGPTL4 would affect lipid levels of mice and monkeys.
They found 1,661 people who were heterozygous for the E40K variant and 17 who were homozygous for it, as well as 75 who had 13 other inactivating ANGPTL4 mutations.
Compared with noncarriers, carriers of the E40K variant had 13% lower triglycerides (P = 2 x 10-23) and 7% higher HDL (P = 1.6 x 10-17), they found.
Dewey and colleagues also determined that carriers of the E40K variant were less likely than noncarriers to have CAD (OR = 0.81; 95% CI, 0.7-0.92).
People with CAD (13 of 10,552; cumulative allele frequency, 0.06%) were less likely than people without CAD (58 of 29,223; cumulative allele frequency, 0.1%) to carry an inactivating ANGPTL4 mutation, according to the researchers, who also found that after adjustment for age, sex and ancestry, people with an inactivating mutation had lower odds of CAD compared with those without one (OR = 0.56; 95% CI, 0.32-1). Adjustment for diabetes, smoking and hypertension did not change the results.
When the researchers administered a monoclonal antibody to mice and monkeys to inhibit ANGPTL4, the result was a reduction in triglyceride levels.
A viable approach?
In a related editorial, Sander Kersten, PhD, wrote that “in combination with extensive recent data on other genetic variants that modulate plasma triglyceride levels, the studies suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk [for CAD].”
Kersten, from the division of human nutrition at Wageningen University in the Netherlands, concluded that the studies “not only improve our understanding of elevated triglycerides in heart disease but also provide a path to the development of future therapies for dyslipidemia.” – by Erik Swain
References:
Dewey FE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1510926.
Kersten S. N Engl J Med. 2016;doi:10.1056/NEJMe1601117.
Disclosure s : The study by the Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia investigators was funded primarily by the NIH. The study by Dewey and colleagues was funded by Regeneron. Dewey is an employee and stockholder of Regeneron. Please see the full studies for a list of the other researchers’ relevant financial disclosures. Kersten reports no relevant financial disclosures.