Lp(a) Gene Variant Associated With Aortic Stenosis

February 06, 2013

MONTREAL, Quebec — An international consortium has identified a variation in the gene coding for lipoprotein (a) (Lp[a]), which appears to be strongly associated with aortic-valve calcification [1]. People carrying this single nucleotide polymorphism (SNP) had a doubling of the risk of valve calcification on computer tomography (CT) compared with those without the variation, report Dr George Thanassoulis (McGill University Health Center, Montreal, QC) and colleagues in the February 7, 2013 issue of the New England Journal of Medicine.

The same SNP has previously been identified as a risk factor for increased Lp(a) levels and coronary artery disease (CAD), so "the cumulative findings support the proposition that a common genetic defect in lipid metabolism underlies the pathogenesis of both atherosclerosis and aortic stenosis," says Dr Gerald W Dorn (Washington University School of Medicine, St Louis) in an accompanying editorial [2].

Although increased levels of Lp(a) have previously been associated with aortic-valve disease, prior observational studies couldn't prove that it was a contributing factor rather than just a marker. These results provide the first evidence for a causal relationship between Lp(a) and calcific aortic-valve disease, say the researchers.

Senior author Dr Wendy Post (Johns Hopkins University of Medicine, Baltimore, MD) told heartwire : "The main implications of this are understanding better about the biology of what might lead to aortic-valve calcification and potentially progression to clinical aortic stenosis. This may lead to new therapies that could perhaps delay progression of aortic stenosis."

Genomics expert Dr Eric Topol (Scripps Translational Research Institute, La Jolla, CA), who was not involved with this study, says: "This is an elegant and important genomic discovery in cardiovascular medicine. The large network of collaborators has connected the dots between atherosclerosis and aortic-valve calcific stenosis, a process that was thought to be interconnected but now via a defined pathway."

Association Affects 13% of Whites But Is Found in All Ethnic Groups

Thanassoulis and colleagues note that aortic stenosis is the third most prevalent form of cardiovascular disease in the Western world, after hypertension and CAD, and is caused by calcification and hardening of the aortic valve, impeding blood flow from the heart to the rest of the body, leading to chest pain, loss of consciousness, and shortness of breath. In severe cases, patients require aortic-valve replacement. Currently, there are no medical treatments to prevent this disease, which mainly affects people over the age of 60.

In their genomewide association study, the team first looked at 2.5 million SNPs among more than 6900 people of white European descent and found that a variant in the Lp(a) locus--rs10455872--reached genomewide significance for the presence of aortic-valve calcification on CT scan (odds ratio per allele 2.05; p=9x10-10). This finding was replicated in an additional 2000 people of Hispanic origin, about 2500 African Americans, and more than 700 Germans (p<0.05 for all comparisons).

The prevalence of the SNP is about 13% in the white population and slightly less in other ethnic groups, Post says.

All had previously undergone a CT scan to look for the presence of aortic-valve calcium and were participants in several ongoing studies--the Multi-Ethnic Study of Atherosclerosis (MESA); the Framingham Heart Study; the Age, Gene/Environment Susceptibility (AGES) study in Iceland; and the Heinz Nixdorf RECALL study in Germany.

In further prospective analyses, the researchers were also able to demonstrate an association between the variant and incident aortic stenosis (hazard ratio per allele 1.68) as well as aortic-valve replacement (hazard ratio 1.54) among more than 28 000 people in Sweden. The association with aortic stenosis was also replicated in an independent Danish cohort.

Topol says the research not only shows that a common variant in Lp(a) is implicated but that this was indeed "a driver of the process." However, "there are some key unknowns, too," he adds. "Clearly, there are other genomic variants that pose a risk for this condition that are not yet known (albeit may be low frequency or rare)."

Findings Could Reawaken Interest in Therapies Targeting Lp(a)

Expanding upon the implications of the research for heartwire , Post said: "The idea is not specifically to predict who is going to develop aortic stenosis, although this is a pretty large effect--it's a doubling of the odds of having aortic-valve calcium. Since Lp(a) predicts risk for myocardial infarction and now we know it also predicts risk for aortic stenosis, we are hoping that maybe pharmaceutical companies will advance their research into compounds that can lower Lp(a), because drugs like statins don't."

One compound that does lower Lp(a) is niacin, she noted, but this has recently suffered a huge setback in the wake of the HPS-2 THRIVE results. Estrogen also lowers Lp(a) but again has suffered from controversy, she notes.

Topol added: "We don't know whether niacin or other Lp(a) antagonists will prevent the process in the individuals at risk. But with this paper, there's great substrate to work with."

Thanassoulis or his institute has received grants from the Canadian Institute for Health Research and the Fonds de Recherche en Santé du Quebec and payment for lectures including service on speaker's bureaus from Servier Canada. Post's institution has received a grant from the National Institutes of Health. Disclosures for the coauthors are provided with the full text of the article at NEJM.org . Dorn has no conflicts of interest.