The traditional view of atrial fibrillation (AFib) is that the arrhythmia is side passenger to other forms of heart disease. However, like so many health-related traits, AFib can often be traced through an individual's genetic composition. To date genome-wide association studies have identified nine susceptibility regions on eight chromosomes that implicate genes encoding transcription factors involved in cardiopulmonary development, cardiac expressed ion channels, and other signaling molecules in the pathogenesis of AFib.

An extensive study published Jan. 29 in the Journal of the American College of Cardiology sought to gain a better understanding of the condition's genetic susceptibility signals and examine their relationship with AFib risk, and found "the chromosome 4q25 AFib locus is architecturally complex and harbors at least four AFib susceptibility signals in individuals of European ancestry." Further, similar polygenic AFib susceptibility was found among European and Japanese populations.

Employing two complementary methods, researchers led by Steven Lubitz, MD, MPH, Cardiovascular Research Center, Massachusetts General Hospital, systematically searched for multiple AFib susceptibility signals at nine genome-wide associated loci in a total of 64,683 individuals of European ancestry. Their findings demonstrated the presence of at least four distinct AFib susceptibility signals in a large intergenic region on chromosome 4q25. In an independent Japanese sample, the researchers observed near identical findings, suggesting that the genetic risk markers for AFib may be generalizable beyond populations of European ancestry.

While the researchers were not able to find evidence for multiple genome-wide significant susceptibility signals at AFib loci other than chromosome 4q25, their findings extend previous reports about the relationship between genetic markers and AFib risk, underscoring its complex nature.

Moving forward, "future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AFib, and explore whether AFib susceptibility signals classify individuals at risk for AFib and related morbidity," the researchers note.

Dan Roden, CM, MD, professor of medicine and pharmacology, Oates Institute for Experimental Therapeutics, writes in an editorial comment, "Although many details remain to be worked out … there is every reason to hope that understanding the mechanism whereby these alleles so consistently confer risk will then inform development of targeted and effective therapies for treatment and more importantly for prevention of the arrhythmia. Biomarkers based on this new understanding could be deployed to identify patients at very high risk of arrhythmia prior to development of the first episode. New drugs can and should be developed to treat and prevent the arrhythmia. A new biology, relating the risk alleles to other emerging factors, such as atrial fibrosis, should emerge. Thus, AFib genomics has every potential to inform not only treatment of AFib but its prevention. Focusing on using fundamental new knowledge to develop ways to prevent the onset of the arrhythmia … does not seem completely unrealistic, and holds out the hope that AFib will not become the epidemic that many have predicted as the population ages."

Keywords: Risk, Genome-Wide Association Study, Genetic Predisposition to Disease, Transcription Factors, Genetic Markers, Chromosomes