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Damaging mutations in ABCA1, APOA1 linked to atherosclerosis

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PHILADELPHIA — In patients with low HDL, a damaging mutation in ABCA1 or APOA1 is associated with an increased risk for subclinical atherosclerosis compared with patients without a mutation, according to a poster presentation at the National Lipid Association Scientific Sessions.

Liam Brunham, MD, PhD, assistant professor of medicine at the University of British Columbia and a principal investigator at the Centre for Heart and Lung Innovation, said the lack of approved therapies have made low HDL a common, but challenging scenario for clinicians. Many of these patients with low HDL have a damaging mutation in the ABCA1 or APOA1 genes.

“Of course we know that low HDL is common amongst individuals with premature CVD, but there is controversy and perhaps uncertainty about the causal relationship between HDL and atherosclerosis,” Brunham said in his presentation. “What we do know... is that many individuals with low HDL have a mutation — typically a rare variant in genes that also cause the very rare Mendelian forms of HDL, in particular, ABCA1 and APOA1 — and there’s conflicting reports on risk of CVD in individuals who have these mutations.”

Researchers recruited 60 patients (14 women; mean age, 54 years) with HDL levels below the 10^th percentile from a specialty lipid clinic to determine whether patients with genetically determined low HDL have a higher prevalence of atherosclerotic CVD compared with those without a genetic mutation.

To identify pathogenic variants and capture the coding regions in ABCA1 or APOA1 genes and, patients received targeted next-generation sequencing (NGS).

Researchers then performed a retrospective chart review to determine clinical atherosclerotic CVD or subclinical disease.

Patients with clinical atherosclerosis and/or a score of 1 in at least one of the subclinical tests was considered to have evidence of atherosclerosis.

Brunham said 24% of patients presented with a disease-causing or likely pathogenic variant in either gene.

A total of 70% of patients with ABCA1 or APOA1 damaging mutations had evidence of atherosclerosis compared with 40% in patients who did not present with the mutations (P = .03).

The researchers found that patients with mutations had reduced cholesterol efflux capacity compared with those without a mutation (26.1% vs 30.7%; P = .02).

“Compared to patients with low HDL without such a mutation, these patients have increased prevalence of atherosclerosis,” Brunham said. “These results support the investigation of therapies to increase cholesterol efflux in patients with genetically low HDL.”

The abstract was chosen as the first-place winner of the Young Investigator Competition. – by Dave Quaile

Reference:

Brunham L, et al. Increased Prevalence of Subclinical Atherosclerosis in Individuals with Damaging Mutations in ABCA1 and APOA1. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Cardiology Today could not confirm relevant financial disclosures.