Gene Variant Tied to Lower Non–HDL-Cholesterol Levels, CAD Risk

Marlene Busko

May 21, 2016

THOUSAND OAKS, CA — In a genetic study of Icelanders, researchers discovered a rare mutation in the ASGR1 gene that was associated with a 30% lowering in non–HDL-cholesterol levels and a reduced risk of coronary artery disease (CAD)[1].

The study by Dr Paul Nioi (deCODE Genetics-Amgen, Thousand Oaks, CA) and colleagues was published May 18, 2016 in the New England Journal of Medicine.

Researchers found that about 0.8% (1/120) of Icelanders, a slightly lower proportion of Danes, and a slightly higher proportion of Dutch people had the mutation, Dr Anne Tybjærg-Hansen (University of Copenhagen, Denmark), who wrote an accompanying editorial[2], explained to heartwire from Medscape.

In a follow-up analysis of individuals from five European-ancestry populations, having a deletion (del12) in ASGR1—a gene that encodes the major subunit of the asialoglycoprotein receptor—was associated with a 34% lower risk of CAD, which is larger than what would be expected from the observed 0.4-mmol/L reduction in non-HDL cholesterol, she noted.

The discovery is a "reasonably big" finding, because it is a new gene mutation with a large reduction in risk of CAD, "but not as large as for APOC3 inhibition," according to Tybjærg-Hansen. However, "we don't know nearly enough about the mechanism yet" to speculate how future drug therapies might be developed stemming from this discovery, she cautioned, adding that "more studies are needed."

Moreover, it is unlikely that such a drug would replace statins or PCSK9 inhibitors. "My guess is that blocking this receptor might be less specific than blocking HMG-CoA reductase or PCSK9, or ApoC3 for that matter," she speculated.

Seeking Genetic Variants that Affect Non-HDL Cholesterol

Non-HDL cholesterol (total cholesterol minus HDL cholesterol) is a better predictor of cardiovascular risk than LDL cholesterol, because it encompasses all cholesterol-containing proatherogenic lipoproteins, including LDL cholesterol, very-low-density lipoprotein, intermediate-density lipoprotein, lipoprotein(a), and chylomicron, Nioi and colleagues write.

To search for new genetic variants that affect non-HDL cholesterol levels, researchers sequenced the genomes of 2636 Icelanders and discovered the rare noncoding deletion in ASGR1.

They also observed that loss-of-function ASGR1 variants were associated with a nearly 50% increase in plasma alkaline phosphatase levels and a smaller increase in vitamin B12.

Researchers then assessed the effects of a loss-of-function ASGR1 variant on the risk of CAD in 42524 cases and 249,414 controls from five European ancestry populations.

"We found that the ASGR1 and del12 variant, like variants in ANGPTL4 and LPA, has a larger effect on the risk of coronary artery disease than is predicted by its effect on levels of non-HDL cholesterol, which suggests that the atheroprotective effects of del12 go beyond the lowering of serum cholesterol levels," Nioi and colleagues summarize.

"We propose that the loss-of-function ASGR1 variants probably exert these 'opposite effects' (ie, increased alkaline phosphatase and vitamin B12 levels and decreased non–HDL-cholesterol levels) through different mechanisms," they write.

According to Tybjærg-Hansen, the findings suggest that del12 protects against atherosclerosis through mechanisms other than its effect on non-HDL cholesterol—possibly by reducing inflammation. However, she emphasize that we "need to know more about the mechanism," before we can speculate on possible clinical implications or potential future drug development.

The study was supported by grants from the Clinical and Translational Science Award program of the National Institutes of Health, National Heart, Lung, and Blood Institute, and Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities to Emory University, and an unrestricted donation from the Novo Nordisk Foundation to the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, and grants from the British Heart Foundation. Nioi reports personal fees from Amgen outside the submitted work and a pending patent related to ASGR antigen-binding proteins. Disclosures for the authors are listed on the journal website. Tybjærg-Hansen has no relevant financial relationships.

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