Lower CAD Risk Hinted With Gene Variants Linked to Lower Triglycerides

Deborah Brauser

March 03, 2016

TARRYTOWN, NY and ST LOUIS, MO — Loss-of-function gene variants associated with lower triglyceride levels also seem to have an effect on clinical outcomes, in that they were associated with a significant drop in coronary artery disease risk, according to two new studies published online March 2, 2016 in the New England Journal of Medicine.

The first analysis[1], from Dr Frederick E Dewey (Regeneron Genetics Center, Tarrytown, NY) and colleagues, assessed almost 43,000 participants from the DiscovEHR human genetics study. It showed that those who had the inactivating angiopoietin-like 4 (ANGPTL4) mutation known as E40K had a 7% higher level of HDL-C, a 13% lower level of triglycerides (TG), and a 19% lower risk for CAD vs those who didn't carry the mutation.

In separate analysis that tested inhibition of ANGPTL4 by using the human monoclonal antibody REGN1001 (Regeneron Pharmaceuticals) in animals, the researchers also found lowered TG levels—but with side effects of mesenteric lymphadenopathy in some of the subjects.

The second study[2], by investigators led by Dr Nathan O Stitziel (Washington University School of Medicine, St Louis, MO), examined records for more than 193,000 individuals. It also showed decreased TG levels and increased CAD protection in those with vs without ANGPTL4 mutations.

Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) told heartwire from Medscape that these are "two very impressive reports" about the ANGPTL4 gene, which was already known to modulate TG levels. "But now we know there are low-frequency loss-of-function variants that can substantially lower the triglyceride level." And this is accompanied by a reduction of at least 15% in CAD, "which is confirmed in both reports," he said via email.

"The question is whether an antibody that achieves the loss of function—and also lowers TG—can be safely given to achieve lower coronary disease," said Topol, an authority on the genetics of heart disease. "So far there have been side effects in mice and primates . . . so it's too early to know whether this has therapeutic value."

ANGPTL4 Inhibition

Normally functioning ANGPTL4 inhibits lipoprotein lipase (LPL), an enzyme that can reduce triglycerides. High levels of TG have been found to be a risk factor for ischemic CVD.

In the first study, the investigators examined ANGPTL4 samples from 42,930 individuals (59% women; mean age 58 years). They then focused on assessing the possible link between the E40K mutation and CAD in 10,552 participants with CAD and 29,223 healthy controls. Of these, 1661 were found to be heterozygous for the E40K variant and 17 were homozygous.

The triglyceride levels were significantly lower in E40K heterozygotes (115 mg/dL) and homozygotes (81 mg/dL) vs noncarriers of the variant (132 mg/dl), and the HDL-C levels were significantly higher (52 mg/dL and 77 mg/dL vs 48 mg/dL, respectively).

When both groups of E40K carriers were combined, they had an age- and sex-adjusted odds ratio (OR) of 0.81 for CAD compared with the noncarriers (95% CI 0.7–0.9, P=0.002).

The 75 participants who were heterozygous for 13 other ANGPTL4 inactivating mutations also had significantly lower triglyceride and higher HDL-C levels vs noncarriers (P=0.02 and P=0.009, respectively). Their OR for CAD vs noncarriers was 0.56 (P=0.05).

New Therapeutic Pathway?

In the animal analyses, REGN1001 showed a "rapid and sustained reduction in plasma triglyceride levels for the 17-day duration" of the assessment in male mice, report the investigators. However, in 21 of the subjects treated with multiple doses of the antibody, "we observed accumulation of lipid-filled Touton cells and lesions in the mesenteric lymph nodes."

Four of five obese rhesus monkeys with dyslipidemia that received the antibody had a 60% decrease in triglyceride levels. And triglyceride levels were significantly lowered in REGN1001-receiving cynomolgus monkeys, albeit with lipid accumulation in the mesenteric lymph nodes of four of the 10 females.

"It is not clear whether therapeutic antagonism of ANGPTL4 will have similar effects in humans," note the researchers. When further investigating electronic health records, they found that the E40K carriers did not have high rates of any abdominal disorders.

"Even if the potential benefits of ANGPTL4 blockade turn out to be limited by the risk of lymphadenopathy in humans, similar therapeutic benefits may still be achieved by blocking ANGPTL4-related proteins, such as ANGPTL8 and ANGPTL3, neither of which appears to be associated with [this adverse effect] in animals," they write.

In an accompanying editorial[3], Dr Sander Kersten (Wageningen University, the Netherlands) notes that "it is unfortunate" that serum amyloid levels weren't measured in either the humans or monkeys that carried the variant. "In mice lacking ANGPTL4, elevated plasma serum amyloid is an excellent early diagnostic tool to predict increased rates of inflammatory complications and death," he writes.

Favorable Profiles and Protection

In the second paper by Stitziel et al, DNA coding was examined for up to 72,868 CAD patients and 120,770 controls.

Carriers of "low-frequency missense variants" in the SVEP1 gene had an increased risk for CAD vs noncarriers (OR 1.14) and carriers of ANGPTL4-inactivating variants had a lower risk (OR 0.86). Those with the ANGPTL4 variants also had a 35% lower level of TG (P=0.003).

Finally, CAD risk was higher in those with inactivating variants in LPL (OR 1.13) and was lower in those with "gain-of-function" LPL variants (OR 0.94).

Dewey et al note that the overall results from both of the newly published studies show "independent allelic evidence that the genetic loss of ANGPTL4 function confers favorable lipid profiles and protection from coronary artery disease."

"We arrived at the same conclusion in different ways," added Dewey to heartwire . "They specifically looked at exomewide or genetic mutations that might either raise or lower risk of [CAD]." And their findings about the gene variants "are very consistent with our findings," he said.

"This provides further support for modulation of ANGPTL4 and points toward a therapeutic opportunity."

Additional Therapies Needed

Kersten agrees, writing in his editorial that "although statin therapy provides us with a means to correct dyslipidemia and to reduce cardiovascular risk, there is a need for additional therapies."

He adds that the question of whether increased TG levels and reduced HDL-C really do increase CHD "has remained a contentious issue." But now both groups of researchers have shown that TG plays "a causal role" in the disease.

"These two studies that identify ANGPTL4 as a link between triglycerides and coronary heart disease not only improve our understanding . . . but also provide a path to the development of future therapies for dyslipidemia," Kersten concludes.

The study by Dewey et al was funded by Regeneron Pharmaceuticals. The Stitziel study was supported in part by a career development award from the National Heart, Lung, and Blood Institute and by the Foundation for Barnes-Jewish Hospital. Dewey reports receiving personal fees and other support from Regeneron outside the submitted work; disclosures for the coauthors are listed on the journal website. Stitzel reports receiving grant support from the National Institutes of Health, grant and nonfinancial support from AstraZeneca, and personal fees from American Genomics and Aegerion Pharmaceuticals; disclosures for the coauthors are listed in the article. Kersten reports receiving grant support from the Leducq Foundation, the European Foundation for the Study of Diabetes, the Netherlands Heart Foundation, and the Netherlands Organization for Scientific Research. Topol is editor in chief of Medscape. He has served as a director, officer, partner, employee, advisor, consultant, or trustee for Apple, AltheaDX, Biological Dynamics, Dexcom, Edico Genome, GenapSys, Gilead Sciences, Google, Illumina, Molecular Stethoscope, Myokardia, Quest Diagnostics, and Walgreen Company. He has received research grants from the National Institutes of Health and Qualcomm Foundation.

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