–May have stronger impact than PCSK9 variants on disease risk
A large new study from Iceland has identified variants in a gene that appear to have powerful cardioprotective effects, perhaps an first early step toward a novel therapy for heart disease prevention and treatment.
The gene, ASGR1, was identified by the well known genetic researcher Kari Stefansson, MD, and his company, deCODE Genetics, a fully-owned subsidiary of Amgen. Using genetic data from the Icelandic population they found ASGR1 variants that had a significant favorable impact on lipid levels and coronary artery disease.
Results of the study were published online in the New England Journal of Medicine.
The ASGR1 gene encodes for a protein involved in the regulation of non-HDL cholesterol levels, though its precise mechanism of action is unknown.
The Icelandic researchers found several variations in ASGR1 that had significant effects on non-HDL cholesterol levels. One 12-base-pair deletion, seen in about 0.8% of the study population, was associated with a 13.6 mg/dL reduction in non-HDL cholesterol, or a 9% relative reduction. This included a 7% reduction in LDL cholesterol and a 6.1% reduction in triglycerides. People with this mutation had a 34% lower risk of coronary artery disease. A second rare variant (found in 1 in 1,850 persons) had an even larger effect on non-HDL cholesterol levels.
In an accompanying editorial, Anne Tybjaerg-Hansen, MD, DMSc, of the University of Copenhagen, wrote that the finding “may suggest a new path to the development of future therapies for the prevention of coronary artery disease.” But, she notes, the “mechanisms by which loss-of-function mutations in ASGR1 cause large reductions in cardiovascular risk remain to be determined.”
Tybjaerg-Hansen wrote that the reduction in coronary risk observed in the study “is considerably larger than that associated with other genetic variants (e.g., PCSK9 mutations) and yet has a relatively lesser effect on non-HDL cholesterol levels.” This suggests that the mutation works “against atherosclerosis through mechanisms independent of those governing non-HDL cholesterol levels. One such mechanism could be reduced inflammation owing to the lower triglyceride levels.”
“This is yet another outstanding scientific observation” from this group, said Sekar Kathiresan, MD, of the Broad Institute in Cambridge, Mass. This study “adds to considerable genetic evidence that blood cholesterol carried in apoB-containing lipoproteins (LDL, VLDL, chylomicron remnant, and Lp(a)) is a key driver of atherosclerosis.”
He noted that this is now the “sixth example of mutations which reduce apoB-containing lipoproteins and confers ‘resistance’ to heart attack.” The previous examples are PCSK9, LPA, APOC3, ANGPTL4, and NPC1L1, the last three of which were found by Kathiresan’s group. Although he said it is still extremely early in the process, the work “suggests that a medicine which mimics the protective mutation should reduce risk for heart attack.”
An Amgen representative said that the company was “well underway” in identifying a molecule to study. “The insights of this latest deCODE study represent a significant advance in understanding how genetics play a role in coronary heart disease. It underscores Amgen’s strategy to focus on the biology of target selection first, with modality considerations second,” said Sean Harper, Amgen’s executive vice president of R&D, in a statement. “We are well underway in developing a molecule for the clinic and actively working to better understand the underlying biology of ASGR1.”