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GWAS Links Lipoprotein(a) Gene Variant to Aortic Valve Calcification, Aortic Stenosis

NEW YORK (GenomeWeb News) – A lipoprotein(a) gene variant is associated with an increased risk of aortic valve calcification and aortic stenosis, researchers led by Wendy Post, an associate professor of medicine and epidemiology at Johns Hopkins University, reported in the New England Journal of Medicine yesterday.

Through a genome-wide association study of more than 6,900 participants of white European ancestry, the researchers linked a SNP in intron 25 of the Lp(a) gene to aortic valve calcification. That association was then replicated in a separate European cohort as well as in about 2,000 people of Hispanic origin and 2,500 African Americans. Additionally, in a prospective study, the SNP was associated with future development of stenosis.

"We found that an unusual type of cholesterol called lipoprotein (a) or Lp(a) — that is not normally screened for in current clinical practice — appears to be a cause of aortic valve disease," George Thanassoulis, an assistant professor of medicine at McGill University and a study co-lead author, said in a statement.

Such aortic calcification was known to run in families, the researchers noted, but the root genetic cause was not known. Additionally, Lp(a) levels have previously been linked to aortic valve disease, but whether it was a driver or byproduct of the disease was also not known.

In this study, researchers searched for SNPs linked to aortic valve calcification, as determined by a CT scan which captured preclinical disease, in three independent cohorts of people of white European ancestry enrolled in the Framingham Heart Study, Gene/Environment Susceptibility-Reykjavik Study, and the Multi-Ethnic Study of Atherosclerosis. One SNP, rs10455872, met genome-wide significance.

That association was then replicated in a separate cohort of white Europeans, and also in cohorts of African Americans and of Hispanic Americans; it did not replicate in a group of Chinese Americans, though the researchers noted that the power of that test was limited by the sample size.

Additionally, in the two cohorts for which the researchers had Lp(a) concentration data, they found that the SNP was strongly associated with Lp(a) levels and that, in turn, those levels were linked to aortic valve calcification. And when the researchers controlled for Lp(a) levels, the link between the SNP and aortic valve calcification lessened, suggesting that the effect of the SNP is mediated by Lp(a) levels.

Meanwhile, in two other cohorts containing a combined 38,600 people who were followed for a median of 14 years, Post and her colleagues examined whether the Lp(a) variant could predict later aortic stenosis. After controlling for non-genetic factors, such as age, gender, and BMI, they found that the SNP was strongly associated with later development of stenosis and valve replacement surgery.

"The G allele was associated with an increase of 60 [percent] to 68 [percent] per allele in the risk of clinical aortic stenosis, clearly linking genetic variation at the LPA locus with aortic-valve calcification," the researchers reported.

The researchers also uncovered a SNP in their discovery cohort of white Europeans linked to mitral annular calcification, but that SNP didn't replicate in a validation cohort of Europeans, though it did replicate in a cohort of Hispanic Americans.

Overall, the researchers said that their "results suggest that lifelong elevations in Lp(a) levels lead to a markedly increased prevalence of aortic-valve calcification in adulthood and implicate Lp(a) in the development of aortic-valve disease."

Further work needs to be undertaken to determine whether lowering Lp(a) levels can stem the disease, the researchers added.

In an accompanying NEJM editorial, Gerald Dorn, an internal medicine professor at Washington University School of Medicine, noted that the Simvastatin and Ezetimibe in Aortic Stenosis trial found that, while lowering cholesterol levels in the blood led to fewer coronary events, it did not affect aortic valve disease.

However, the study did not take genotypes into account, Dorn said, adding that the minor allele frequency of the variant Post and her colleagues found is 0.03, meaning that it appears in about five or six people out of every 100. "These persons represent a small subgroup of genetically susceptible patients who might benefit from lipid-lowering therapy owing to their genetic predisposition to aortic calcification," he wrote. "New trials are needed to assess this possibility and might best focus on early valve disease."