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Aortic Valve Stenosis GWAS Leads to Loci Also Tied to Heart Development, Atherosclerosis

NEW YORK (GenomeWeb) – A new genome-wide association study has uncovered two new loci with ties to a heart valve disease called aortic valve stenosis (AS). 

As they reported online today in Nature Communications, researchers from Amgen's Decode Genetics, the University of Iceland, and elsewhere compared variant profiles in nearly 2,500 Icelandic individuals with AS and more than 349,300 unaffected controls — an analysis informed by whole-genome sequencing on 15,220 individuals from Iceland and subsequent imputation in 151,678 genotyped Icelanders.

After validation testing on another 4,850 cases and 451,731 controls with European ancestry, the team was left with one known and two new AS-linked loci. One of the new loci, an AS-associated variant near the PALMD gene on chromosome 1, also showed ties to heart traits such as bicuspid aortic valve malformations and aortic root diameter. A second new AS-associated site involved a variant in chromosome 2 gene TEX41 that has its own associations with bicuspid aortic valve and coronary artery disease (CAD).

"The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS," Decode Genetics researcher Anna Helgadottir, the study's co-corresponding and first author, and her colleagues wrote, noting that "several pathways are shared by CAD and AS."

Some of the clinical risk factors for conditions such as atherosclerosis are known to overlap with aortic valve calcification, one of the features that can interfere with outflow from the heart's left ventricle in AS, the team noted. The pathogenesis and genetic basis of AS are not well understood, though prior GWAS highlighted a variant associated with  aortic valve calcification in the apolipoprotein(a) gene LPA, along with variants linked to AS and several other heart-related conditions.

For their new GWAS, Helgadottir and her colleagues compared around 32.5 million sites in the genomes of 2,457 genotyped individuals from Iceland with AS and 349,342 unaffected controls, using variants imputed from 15,220 sequenced Icelanders and 151,678 genotyped, long-range-phased individuals from the same population.

After taking seven common and lower-frequency variants forward for testing in another 4,850 individuals with AS and 451,731 unaffected controls from Sweden, Norway, the US, and the UK, the team validated associations between the PALMD-neighboring variant, a variant in the intron of TEX41, and the previously described association with a variant in the apolipoprotein(a) gene LPA.

The same three loci also appeared to be linked to Icelandic AS cases that had been treated by aortic valve replacement surgery, the researchers reported, though the associations appeared to be slightly less significant.

The team's follow-up analyses indicated that two of the three risk loci — in and around PALMD and TEX41 — were associated with bicuspid aortic valve, based on data for more than 1,500 cases and nearly 33,900 controls from Iceland, Sweden, and the US.

And still other overlapping genetic pathways turned up when the group delved into causal AS associations and considered their overlap with other heart/cardiovascular conditions using available data for individuals from Iceland and participants in the UK Biobank.

Based on their findings, the authors noted that "there may be a cause shared by CAD and AS," though they cautioned that "causal analysis suggests that only some genetic pathways are shared by CAD and AS." Moreover, they noted that the risk of both types of disease might be mediated in part by lipoprotein cholesterol levels.

"While our genetic causal analysis does not support a generalized sharing of genetic risk between CAD and AS, it indicates that the shared risk factors of [apolipoprotein(a) and non-high-density lipoprotein] cholesterol contribute substantially to the frequent co-occurrence of these diseases," they concluded.