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Genetic link to aortic stenosis established
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Researchers have discovered a gene associated with a form of cholesterol that increases the risk for developing aortic stenosis by more than half.
“Genetic variation in the LPA locus, mediated by lipoprotein(a) levels, is associated with aortic valve calcification across multiple ethnic groups and with incident clinical aortic stenosis,” George Thanassoulis, MD, and colleagues wrote in The New England Journal of Medicine.
Using CT scanning, the researchers determined genome-wide associations with the presence of aortic valve calcification in 6,942 participants and mitral annular calcification in 3,795 participants. The findings were then replicated in independent cohorts of participants who had CT-detected valvular calcification or clinical aortic stenosis. The analysis included participants of white European ancestry. All participants were from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.
The single nucleotide polymorphism (SNP) rs10455872 in the LPA locus was strongly linked to the presence of aortic valve calcification in this study population (OR per allele=2.05). This finding was replicated in additional cohorts of participants of white European, African American and Hispanic American descent (P<.05 for all). Aortic valve calcification was also associated with genetically determined Lp(a) levels, predicted by LPA genotype, according to study results.
In prospective analyses, the LPA genotype was linked to incident aortic stenosis (HR per allele=1.68; 95% CI, 1.32-2.15) and aortic valve replacement (HR=1.54; 95% CI, 1.05-2.27) in a large Swedish cohort and the link with incident aortic stenosis as replicated in an independent Danish cohort.
Genome-wide significance for mitral annular calcification was achieved with two SNPs — rs17659543 and rs13415097 — near the pro-inflammatory gene IL1F9. However, the researchers noted that these findings were not consistently replicated, according to the abstract.
These data point to the first known cause of aortic stenosis and to a potential treatment to prevent the disease.
“We found that an unusual type of cholesterol called Lp(a) — that is not normally screened for in current clinical practice — appears to be a cause of aortic valve disease,” Thanassoulis, director of preventive and genomic cardiology at McGill University Health Center and assistant professor in medicine at McGill University, said in a press release. “High levels of this type of cholesterol are predicted primarily by an individual’s genetic make-up with only modest influence from lifestyle or other factors.”
According to Thanassoulis, previous studies did not differentiate whether Lp(a) was a cause or a marker of valve disease. “But our results strongly suggest a causal link and add to the mounting evidence that Lp(a) may be an important drug target for cardiovascular diseases,” he stated. The researchers said there is a need for a randomized clinical trial to study whether lowering Lp(a) with other drugs slows valve classification.
“This is an important step forward in understanding the biology of the development of aortic stenosis and how this common genetic variant, which is found in 13% of the general population, contributes to that risk,” Wendy S. Post, MD, cardiologist and associate professor of medicine and epidemiology at the Johns Hopkins University School of Medicine, said in the release. “Advancing age is a major risk factor for aortic stenosis and, with the aging of the population, this will become an even bigger health concern.”
Disclosure: See the full study for a list of relevant financial disclosures and study support.
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