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Coronary Artery Disease Risk, Non-HDL Cholesterol Lower in Europeans with Rare ASGR1 Mutations

NEW YORK (GenomeWeb) – An international team led by investigators at Decode Genetics-Amgen has identified a rare, non-coding deletion in the asialoglycoprotein receptor gene ASGR1 that appears to protect against coronary artery disease in individuals of European ancestry.

As they reported yesterday in the New England Journal of Medicine, the researchers used cues from genome sequences of more than 2,600 individuals from Iceland to impute genetic variant patterns in nearly 400,000 more genotyped Icelanders. Folding in non-high-density lipoprotein (HDL) levels for more than 119,000 Icelandic individuals led them to a truncating non-coding deletion in ASGR1 that was linked to lower-than-usual non-HDL cholesterol levels.

The team subsequently saw ties between the same ASGR1 variant and reduced coronary artery disease risk when it considered genetic data from tens of thousands of Europeans with coronary artery disease and almost 250,000 without. Likewise, another look at the Icelandic population unearthed a second loss-of-function change to the gene that was also associated with diminished non-HDL cholesterol levels.

Together, the study's authors noted, the results suggest that ASGR1's protein product plays a role in the levels of non-HDL cholesterol and other asialoglycoproteins in ways that impact heart disease risk.

"[W]e have identified rare loss-of-function variants in ASGR1 that are associated with lowering of non-HDL cholesterol levels and a reduced risk of coronary artery disease," co-corresponding authors Kari Stefansson and Unnur Thorsteinsdottir, with Decode Genetics-Amgen, and their colleagues wrote. "These variants disrupt ASGR1 function and represent a link between the sialylation pathway and atherosclerotic diseases."

Past studies suggested that non-HDL cholesterol entities such as low-density lipoprotein, very-low-density lipoprotein, or intermediate-density lipoprotein cholesterol are more accurate predictors of cardiovascular risk than LDL cholesterol alone, the team explained, prompting interest in genetic factors that mediate non-HDL levels.

To that end, the researchers used tens of millions of variants detected in 2,636 sequenced Icelander genomes to impute variants in some 398,000 other Icelanders — a group that included 119,146 individuals with documented non-HDL cholesterol blood serum levels.

Using variant data for the cholesterol-profiled participants, the team detected a potential association between non-HDL cholesterol levels and seven non-coding variants at a chromosome 17 locus encompassing the ASGR1 and ASGR2 genes.

When they took a closer look at this site, the researchers found that the variants tagged an ASGR1 deletion that seems to activate a cryptic splice site, leading to a truncated version of the protein that's susceptible to protein degradation, the study's authors explained.

The deletion effectively knocks out one copy of ASGR1, which codes for a hepatic asialoglycoprotein receptor and is known for its role in degrading desialylated glycoproteins. The team recapitulated the association with non-HDL cholesterol in individuals in Denmark and the Netherlands, before going on to search for ties to coronary artery disease itself.

In data for 33,090 coronary artery disease cases and 236,254 controls from Iceland and more than 20,000 cases or controls from the US, UK, New Zealand, and Denmark, the researchers saw diminished heart disease risk in carriers of the ASGR1 deletion.

Likewise, coronary artery disease risk was dialed down in individuals from Iceland who carried a second loss-of-function mutation to ASGR1, identified in the sequenced samples from 2,636 Icelanders.