Genetic Control of Left Atrial Gene Expression: A New Window into AFib Risk

A multidisciplinary team of Cleveland Clinic researchers has gained new insight into common genetic variants associated with atrial fibrillation (AF), reveals a recent report in Circulation: Genomic and Precision Medicine.

Although it’s widely accepted that AF has a strong heritable component, to date there has been little understanding of how certain common genetic variants increase disease risk. Previous genome-wide association studies (GWAS) revealed 23 chromosomal regions (loci) connected with AF risk. The new Cleveland Clinic study narrowed the focus to identify specific genes and genetic variations that are associated with 12 of these loci, which can alter proper function of the left atrium.

LAA tissue from 265 heart surgery patients

In search of the missing link between the GWAS-identified loci and their related AF genes, the research team collected and analyzed left atrial appendage (LAA) tissue from 265 patients who underwent elective cardiac surgery to treat AF, valve disease or other cardiac disorders.

They compared the association of LAA gene expression with single-nucleotide polymorphisms (SNPs), common genetic variants that sometimes affect gene expression or function. The researchers used RNA sequencing technology to characterize gene expression profiles for more than 24,000 protein coding and noncoding RNAs that are expressed in LAA tissue. Combining this gene expression data with the SNP data, they looked for associations between those that occurred nearby one another, paying close attention to the 23 GWAS-identified SNPs that had previously been associated with AF.

A genome-wide catalog

Analyses revealed that 12 of the AF-associated SNPs were related to the LAA expression of a nearby gene (these SNP-gene pairs are called cis-expression quantitative trait loci, or cis-eQTLs). It is suspected that cis-eQTL genes may be responsible for the association with AF, even if a gene of that type is not the closest gene to the GWAS SNP.

Looking genome-wide, the researchers discovered that common SNPs were significantly associated with the expression of more than 16,000 local genes in LAA tissue. They cataloged the LAA cis-eQTLs and created a publicly available and searchable database to help facilitate and fast-track future studies related not only to AF but also other cardiovascular traits and diseases. Additional research will be important to further investigate how the cis-eQTL SNPs regulate gene expression and how the changes in specific gene expression increase a patient’s risk for developing AF, presumably by altering atrial cell structure, function or both.

Potential clinical payoffs

The researchers believe these findings will have important implications for developing new AF drugs that target the genetic variants and cellular processes involved. “While several tests can diagnose atrial fibrillation after disease onset — including ECG, stress testing and echocardiography — identification of these genetic variants may open the door to a genetic panel that can assess patient risk for atrial fibrillation and inform tailored prevention and treatment strategies,” says Cleveland Clinic cardiologist Mina Chung, MD, one of the study’s primary authors.

“Atrial fibrillation affects millions of Americans, and the genetic causes remain elusive,” adds co-author A. Marc Gillinov, MD, Chairman of Thoracic and Cardiovascular Surgery at Cleveland Clinic. “Important studies like this one will help us to understand genetic risk and, ultimately, prevent development of this common arrhythmia.”

The study was supported by the National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Sciences; the National Institute of General Medical Sciences; Cleveland Clinic Department of Cardiovascular Medicine philanthropy research funds; and the Tomsich Atrial Fibrillation Research Fund.