Novel protective gene against CAD uncovered

By Eleanor McDermid

A large study has found that mutations in the gene encoding the major subunit of the asialoglycoprotein receptor (ASGR1) are protective against coronary artery disease (CAD).

"These variants disrupt ASGR1 function and represent a link between the sialylation pathway and atherosclerotic diseases", write the researchers in The New England Journal of Medicine.

Using data from around 400,000 Icelandic people, Kári Stefánsson (deCODE Genetics-Amgen, Reykjavik, Iceland) and co-researchers identified seven variants linked to non-high-density lipoprotein (HDL) cholesterol levels in a region including the genes coding two subunits of the asialoglycoprotein receptor.

The strongest association with lipid levels was for a noncoding 12-base-pair deletion (del12) in intron 4 of ASGR1, which appeared in one in every 120 people. The mutation resulted in a truncated protein, which was easily degraded, causing reduced ASGR levels.

Non-HDL cholesterol levels were 13.6 mg/dL lower in carriers of the del12 variant than in noncarriers, findings that were consistent in approximately 21,000 additional people from Denmark and the Netherlands. The researchers identified an additional loss-of-function mutation in ASGR1, with similar effects, but this was even rarer than del12 and occurred only in the Icelandic population.

Carriers of del12 also had a 34% reduction in the risk of CAD, which the team says is greater than would be expected given the degree of non-HDL cholesterol reduction, and "suggests that the atheroprotective effects of del12 go beyond the lowering of serum cholesterol levels."

The asialoglycoprotein receptor plays a role in degrading desialylated glycoproteins, and indeed, levels of alkaline phosphatase and vitamin B₁₂ were significantly higher in del12 carriers than noncarriers. However, this did not mediate the association between del12 and non-HDL cholesterol levels, and the researchers suggest that del12 affects desialylated glycoproteins and non-HDL cholesterol through different mechanisms.

Writing in an accompanying editorial, Anne Tybjærg-Hansen (University of Copenhagen, Denmark) says that "this association may suggest a new path to the development of future therapies for the prevention of coronary artery disease."

But she cautions that "mechanisms by which loss-of-function mutations in ASGR1 cause large reductions in cardiovascular risk remain to be determined."

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