A Boost for Efforts to Uncover Functional Genomics of Afib

A large proportion of atrial fibrillation (AF) cases are inherited, and genome-wide association studies (GWAS) have identified 14 genetic loci associated with AF. Yet the mechanisms by which these variants increase AF risk remain unknown.

Using stem cells to create cardiac myocytes is one promising model for uncovering such mechanisms, and Cleveland Clinic researchers have received a four-year, $3.1 million R01 grant from the National Heart, Lung, and Blood Institute (NHLBI) to explore that model for insights into the functional genomics of AF in human atria.

“Our overall goal is to identify functional variants in AF-associated loci that alter gene function or expression, and to elucidate those variants’ impact on associated biological pathways,” explains Cleveland Clinic cardiologist Mina Chung, MD, one of the lead researchers on the grant. “This will facilitate the identification of novel targets for AF treatment or prevention.”

Building on previous work

The NHLBI award renews a grant received by the Cleveland Clinic research team four years earlier. Dr. Chung and her partners have been conducting advanced research in this area over the past decade. Other key team members are translational scientists David Van Wagoner, PhD, and Jonathan Smith, PhD, of Cleveland Clinic Lerner Research Institute, and biostatistician/bioinformatician John Barnard, PhD, along with a group of technologists, students and postdoctoral fellows.

With their first grant and additional philanthropic funds, the team contributed to a consortium of investigators studying patients with and without AF to identify single-nucleotide polymorphisms (SNPs) across the human genome that revealed areas of DNA associated with AF. A meta-analysis of these studies published in Circulation in 2014 identified the 14 independent loci associated with AF. Many of the loci were found to be located in noncoding regions near genes that may contribute to embryologic pulmonary vein formation or to electrical triggering, as well as to cellular changes that might promote substrates that propagate AF.

Additional grant funding enables the team to move their findings closer to clinical utility. Using human atrial tissues supplied by collaborating Cleveland Clinic cardiothoracic surgeons, the team employed RNA microarrays and then next-generation RNA sequencing (RNAseq) to conduct genetic-transcriptomic studies to identify the genes, gene networks and cellular functions affected by the DNA regions associated with AF risk.

Next-phase research to use cardiac myocytes from stem cells

With the funds from the 2016 NHLBI grant, the team plans to move their research into cell models. Genetic risk of AF is mediated by changes in the expression of proteins important to maintaining normal cardiac rhythm. Risk variants in the genes encoding these proteins may increase susceptibility to, or progression of, AF.

The team will use stem cells to create cardiac myocytes, and then manipulate the myocytes using molecular methods such as gene editing to better understand the physiology of what’s affected by the genetic variants.

“We will be looking for electrical, biochemical or physiologic differences in myocytes and use editing techniques to move them from higher-risk to lower-risk genetic patterns,” explains Dr. Van Wagoner. “This process will help us better understand the pathways associated with developing AF, facilitating the development of better drugs to treat and prevent AF.”

“Pinpointing the specific mechanism and targets of loci identified by the genomic analysis of AF will bring us closer to clinical application,” adds Dr. Chung.

Image courtesy of Cleveland Clinic Disease Management online textbook.