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New Variants Linked to Atrial Fibrillation Risk

NEW YORK (GenomeWeb) – A pair of studies has uncovered new variants linked to atrial fibrillation risk, including ones that appear specific to East Asian populations.

Atrial fibrillation, a type of cardiac arrhythmia, is estimated to affect more than 33 million people around the world. Slightly more than a dozen variants have been previously associated with atrial fibrillation risk in Europeans and one in Asians.

In two separate studies appearing in Nature Genetics today, researchers have identified additional atrial fibrillation risk variants through meta-analyses and genome-wide association studies to bring the total up to more than two dozen. These newly identified variants included ones specifically associated with atrial fibrillation in a Japanese population.

"Because of the complex [linkage disequilibrium] structure and varying environmental exposures among different populations, it is essential to identify risk factors associated with atrial fibrillation in specific populations, as these could subsequently facilitate better risk prediction for atrial fibrillation in regional clinical settings," researchers led by the Riken Center for Integrative Medical Sciences' Toshihiro Tanaka wrote in their paper.

In the first paper, researchers from the Atrial Fibrillation Genetics (AFGen) Consortium led by the Broad Institute's Patrick Ellinor conducted meta-analyses of genome-wide association studies, exome-wide association studies, and rare variant association studies that drew on some 22,300 people with atrial fibrillation and 132,000 controls. After replication using cases and controls from the BioBank Japan study and the UK Biobank, the AFGen consortium identified 12 new genetic loci linked to atrial fibrillation risk.

Seven of the loci now linked to atrial fibrillation have been linked to related phenotypes like electrocardiographic traits, left ventricle internal diastolic diameter, and stroke, the researchers noted. Additionally, a number of genes near these risk loci encode potassium or sodium channels.

One of the variants Ellinor and his colleagues uncovered — a variant linked to SH3PXD2A — was specific to people of Asian ancestry, they noted.

In a separate paper, Riken's Tanaka and his colleagues conducted a GWAS to search for atrial fibrillation risk variants within a Japanese population that drew on 8,180 cases and 28,612 controls. After follow-up in a further 3,120 cases and 125,000 controls, they homed in on six new loci associated with atrial fibrillation risk, including one near SH3PXD2A.

When they conducted an in silico replication using the AFGen Consortium's GWAS meta-analysis data that consisted of some 16,000 cases and 113,700 controls, Tanaka and his colleagues found that the most significant association was at the SLC1A4-CEP6 locus, whereas other SNPs reached only nominal evidence of association. This suggested to the researchers that there's heterogeneity between the two cohorts.

Overall, Tanaka and his colleagues reported that the most significantly associated locus in their Japanese cohort encompassed the HAND2 gene, which they found harbored two independent association signals. HAND2 encodes a protein involved in cardiac morphogenetics. The minor allele of the variant the researchers associated with atrial fibrillation is more common among East Asians, they added.

Both studies highlighted variants near SH3PXD2A as affecting atrial fibrillation risk among people of Asian ancestry. SH3PXD2A encodes a scaffolding protein involved in the invadosome. In particular, Ellinor and his colleagues noted that SH3PXD2A is expressed in the human atria and ventricles and is important for neural crest migration. Tanaka and his colleagues added that previous work has found that inhibiting SH3PXD2A function affects the regulation of extracellular matrix degradation and axon guidance by growth cone invadosomes.

Both sets of researchers added, though, that more research on the role of SH3PXD2A in atrial fibrillation risk is needed.