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Rare Gene Variants Affect Blood Lipids, Risk of Coronary Artery Disease

NEW YORK (GenomeWeb) – Researchers have uncovered about a dozen new rare genetic variants that influence blood lipid levels.

A team led by DeCode Genetics' Kari Stefansson searched for rare and low frequency variants linked with non-HDL cholesterol, HDL cholesterol, and triglycerides in a cohort of nearly 120,000 Icelanders. As they reported today in Nature Genetics, they uncovered 13 new large-effect variants, including ones in APOB and LDLR, and replicated 14 other variants. Ultimately, when they examined the causality between these variants, lipids, and cardiovascular disease, they uncovered a link between non-HDL cholesterol and coronary artery disease (CAD) pathogenesis.

"[W]e used a large population-based resource of whole-genome sequence data to search for new rare and low-frequency lipid-associated variants that may suggest new therapeutic targets for CAD," Stefansson and his colleagues wrote in their paper. "We subsequently used information on both rare and common variants to dissect the relationship between lipid traits and CAD."

He and his colleagues sifted through the whole-genome sequences of 2,636 Icelanders, and then imputed the data into a large population-based dataset to test for associations with non-HDL cholesterol, HDL cholesterol, and triglycerides. They homed in on rare and low frequency variants whose annotations suggested a moderate or high impact.

They then tested these lipid-linked variants for associations with CAD in 33,090 cases and 236,254 controls, and found 13 rare and low frequency variants that were linked with at least one lipid trait.

All of these variants fell within genes associated with lipid metabolism. For instance, they reported that two variants in CETP were associated with increased HDL cholesterol levels; three rare APOB variants were linked to markedly lower non-HDL cholesterol levels; and two ANGPTL3 variants were linked with decreased triglyceride levels. Some variants affect multiple lipid traits, like one in ZNF285 that affected both triglycerides and HDL cholesterol. The researchers also confirmed 14 variants that had previously been associated with lipid traits.

Of these 27 total rare and low frequency variants, five were also associated with CAD in Icelanders. The LDLR splice donor mutation at rs200238879 leads to a 2.8-fold higher risk of CAD, the authors noted, while another LDLR variant decreased disease risk by nearly a quarter.

Stefansson and his colleagues also constructed genetic risk scores for each lipid trait by drawing on the variants uncovered in their study as well as a further 185 variants previously linked to lipids. Genetic risk scores for non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides all associated individually with CAD, the researchers noted.

The CAD risk associated with LDL cholesterol was fully captured — as expected — by the non-HDL cholesterol risk score. However, that non-HDL cholesterol risk score includes additional risk beyond what LDL cholesterol conferred.

In a joint analysis of non-HDL cholesterol, HDL cholesterol, and triglycerides, the researchers found that only the association of non-HDL cholesterol with CAD remained significant. This, they noted, agrees with the findings of a recent epidemiological study and of a recent genetic study.

In addition, they reported that genetic risk score for non-HDL cholesterol was also associated with CAD diagnosis at an earlier age and shorter lifespan.

Stefansson and his colleagues suggested that the association between triglycerides and CAD could exist because of cholesterol that's carried by triglyceride-rich lipoproteins. Added to the finding that non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol, this could mean that targeting atherogenic cholesterol beyond what LDL particles carry might reduce cardiovascular risk, they wrote.