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Teams Describe Mutations Tied to Lower Triglyceride Levels, Reduced Coronary Artery Disease Risk

NEW YORK (GenomeWeb) – In a pair of studies published online last night in the New England Journal of Medicine, independent research teams described mutations that appear to alter coronary artery disease risk factors.

Those involved in the research are hopeful that the newly identified glitches, which included apparently protective mutations to the angiopoietin-like 4-coding gene ANGPTL4, may help untangle coronary artery disease biology and come up with new treatments for preventing coronary artery disease.

In particular, both teams suspect that there may be a benefit to focusing on a broader pathway containing lipoprotein lipase, a triglyceride-chopping enzyme inhibited by ANGPTL4's gene product and a handful of other proteins. Though LPL activation has been linked to lower-than-usual blood triglyceride levels in the past, the new studies hammer home the potential importance of this triglyceride shift in coronary artery disease risk.

"Now we're understanding that triglycerides are causal, and I think it's going to be a different path for treating … coronary disease," Nathan Stitziel, a Washington University cardiologist, medicine and genetics research, and co-corresponding author on one of the studies, told GenomeWeb.

"[Low-density lipoprotein (LDL) cholesterol] is accepted as a modifiable risk factor for coronary disease," said Regeneron Genetics Center researcher Frederick Dewey, co-first author on the other NEJM paper. "What's been less clear, despite the epidemiological connection between triglycerides and HDL [cholesterol] and coronary disease is whether that risk factor, if modified could lead to a reduction in coronary disease risk."

"This builds a case for additional cholesterol fractions, triglyceride fractions, that might be implicated in coronary disease risk beyond LDL [cholesterol] and points to what we view as a new therapeutic opportunity in the reduction of risk for coronary disease that's … parallel to the therapies that currently exist that target LDL [cholesterol]."

For the first of the studies, Washington University's Stitziel and colleagues did array-based genotyping on 42,335 individuals with coronary artery disease and 78,240 without, focusing on around 54,000 variants in protein-coding sequences from more than 13,700 genes.

Comparing cases and controls, the team identified coronary artery disease associations for low-frequency variants in two genes, LPA and PCSK9, linked to the condition through past studies of common variants. But they also identified potential associations for low-frequency, missense mutations affecting a dozen other genes.

After attempting to verify these new associations with data from the discovery cohort and genotypes for tens of thousands more cases and controls, the researchers were left with low-frequency, missense mutations affecting two genes: SVEP1 and ANGPTL4.

When it scoured available epidemiological data for clues to the functions of one of the coronary artery disease-associated glitches in ANGPTL4, the group found that the mutation coincided with lower-than-usual triglyceride levels and elevated high-density lipoprotein (HDL) cholesterol levels — a finding confirmed through a follow-up search for loss-of-function ANGPTL4 mutations in almost 14,000 thousand myocardial infarction cases or controls.

Though rare overall, loss-of-function ANGPTL4 changes were far more common in unaffected controls than in the heart disease group, for example, turning up in nine of 6,924 myocardial infarction patients, but 19 of 6,834 individuals without. On average, these loss-of-function alleles coincided with a 35 percent dip in blood plasma triglyceride levels.

This effect seemed to depend on lipoprotein lipase, the enzyme inhibited by ANGPTL4's protein product, the researchers explained, since a gain of function glitch in the LPL gene seemed to dial down coronary artery disease risk and a loss-of-function LPL mutation apparently made individuals more prone to the disease.

From the authors' point of view, that highlights the potential for mediating one form of coronary artery disease risk by lowering blood triglycerides through the ANGPTL4-LPL pathway — something that might be accomplished by fiddling with the function of ANGPTL4 or another LPL inhibitor or otherwise boosting LPL activity.

"The strategy would be to increase LPL activity, which may be hard to do directly," Stitziel explained. "But there are natural inhibitors of LPL such as ANGPTL4, APOC3, and ANGPTL3 … If you block those natural inhibitors, you would, in turn, increase LPL activity and, hopefully, decrease risk of coronary disease by lowering triglycerides."

Meanwhile, researchers from the Regeneron Genetics Center, a subsidiary of Regeneron Pharmaceuticals, and Geisinger Health System detected a similar dip in triglyceride levels amongst individuals with inactivating mutations to ANGPTL4 in their own coronary artery disease study.

For that analysis, the team sequenced ANGPTL4 exons in almost 43,000 de-identified individuals of European descent from the DiscovEHR cohort, following up on clues from published research from another team linking inactivating ANGPTL4 mutations to lower blood triglyceride levels and elevated HDL cholesterol.

After observing the same sorts of blood triglyceride and HDL cholesterol shifts in individuals with a missense ANGPTL4 mutation, the researchers set out to search for corresponding ties to coronary artery disease in 10,552 individuals and more than 29,200 control individuals.

Indeed, individuals with the so-called p.E40K mutation in ANGPTL4 — a missense change in the gene that Stitziel and colleagues also detected in their chip genotyped discovery cohort — were roughly 19 percent less likely to experience coronary artery disease than those without the inactivating ANGPTL4 mutation.

With the exon sequence data, Dewey and his colleagues uncovered more than a dozen other loss-of-function mutations affecting ANGPTL4 as well, which once again turned up more often in those without coronary artery disease.

"We were able to demonstrate that that association is one in which ANGPTL4 loss-of-function or other protein-disrupting mutations protects from coronary disease in a large population context," Dewey said. "And we were happy to hear that Nate Stitziel and colleagues, using a somewhat different approach, arrived at the same answer."

Next, the Regeneron and Geisinger team tried treating cynomolgus monkeys, rhesus monkeys, and mice with an ANGPTL4-targeting human monoclonal antibody dubbed REGN1001, developed with the help of Regeneron's proprietary VelociGene platform.

The team did see declines in blood triglyceride levels in these animals. But it remains to be seen whether a similar treatment approach will be suitable in humans, particularly since the mice and monkeys that received repeated REGN1001 doses while on a high-fat diet developed unusual mesenteric lymph node features including lipid accumulation.

Regeneron is pursuing an alternative approach to loosening controls on lipoprotein lipase as well: its antibody REGN1500, also known as evinacumab, targets angiopoeitin-like 3 protein, a lipoprotein lipase inhibitor encoded by the ANGPTL3 gene.

That antibody is currently in stage II development in studies aimed at treating a condition called homozygous familial hypercholesterolemia, Dewey noted, though the team is also doing earlier phase REGN1500 studies centered on other high blood lipid level-related conditions.

"We continue to have a lot of interest in this pathway in general, and what we currently are exploring are other angiopoeitin-like proteins that modulate lipoprotein lipase levels," he said.

In an editorial accompanying the NEJM studies, Wageningen University's Sander Kersten discussed potential pluses and pitfalls of targeting ANGPTL4 as a means of curbing coronary artery disease risk, noting that "[a]though statin therapy provides us with a means to correct dyslipidemia and to reduce cardiovascular risk, there is a need for additional therapies."