Variants that may cause AF risk identified

Researchers have identified causal genes and genetic variants associated with chromosomal regions connected with atrial fibrillation risk.

Mina K. Chung, MD, staff cardiologist in the section of pacing and electrophysiology in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic, and colleagues performed RNA sequencing of left atrial appendage tissues from 265 participants to identify the effect of genetic variants on gene expression to potentially explain the link between genome-wide association loci with AF risk.

Previous genome-wide association studies have identified approximately 100 loci identified with AF, and 23 were known at the time the present study was conducted, Chung told Cardiology Today.

“We were able to test target tissues of interest,” Chung said. “Genome-wide association studies identify single nucleotide polymorphisms (SNPs) associated with the phenotype of atrial fibrillation, but they don’t tell you the causative SNPs. So we did whole-genome RNA sequencing and genotyping. Locus identification is only the start of an arduous process of identifying the causal genetic variants and the mechanisms by which these may increase AF risk. We’ve used transcriptomics to try to make functional links to variants identified in genome-wide association studies. We aimed to identify functional SNPs and mechanisms by which these could affect AF, and then to identify novel upstream therapies for AF. We’re still far away from identifying therapies, but this is one of the first steps toward it.”

Chung and colleagues found that altered expression of the following genes played a role in risk for AF: PRRX1 (chromosome 1q24), SNRNP27 (1q24), CEP68 (2p14), FKBP7 (2q31), KCNN2 (5q22), FAM13B (5q31), CAV1 (7q31), ASAH1 (8p22), MYOZ1 (10q22), C11ORF45 (11q24), TBX5 (12q24) and SYNE2 (14q23).

Unexpectedly, according to Chung, the team did not find significant cis-expression quantitative train loci at PITX2, the gene most strongly identified with AF risk, but that may be due to the location of the tissue samples. “One of our next steps is to look at the regional differences,” she said.

Next, researchers will need to “use these data to target more molecular basic studies looking at the mechanisms,” she said. “This will help researchers look up the SNPs and loci they want to study, and maybe some of the genes involved in AF pathogenesis. It may be able to bring focus to this area.”

In a related editorial, Jason D. Roberts, MD, MAS, from the section of electrophysiology, division of cardiology, department of medicine, Western University, London, Ontario, Canada, wrote that the study “provided important novel insight into the relation between common genetic variation and gene expression within left atrial appendage tissue. ... Much work remains to definitively identify novel disease targets that can be used to guide the development of new treatment strategies.” – by Erik Swain

For more information:

Mina K. Chung, MD, can be reached at chungm@ccf.org.

Disclosure s : The authors and Roberts report no relevant financial disclosures.