Atrial Fibrillation Genetics: Is There a Practical Clinical Value Now or in the Future?

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia and has significant clinical impact. Over the last decade, our understanding of the genetics of AF has expanded dramatically. After a heritable predisposition for AF was identified, many investigators have in turn identified both common and rare variants associated with AF. Ongoing work is focused on translating these variants into disease pathways and novel therapeutic modalities. In this review, we focus on our understanding of the current concepts behind the genetics of AF and outline a vision for the incorporation of genetic data into clinical practice.

Strategies for Risk Analysis and Disease Classification in Atrial Fibrillation

“…As illustrated by Robert et al ., and reviewed recently by Ellinor et al ., the scientific community has never been more suited to begin correlating genetic data in patient populations with disease risk . Public‐access databases are now available to cross‐reference variants with described phenotypes and set the groundwork for such genetic analysis.…”

“…In addition to age, other risk factors for AF include cardiac (sinus node dysfunction, valvular heart disease, cardiomyopathy) and noncardiac (diabetes) phenotypes, as well as environmental factors . Furthermore, while not generally considered an inherited arrhythmia, there are now significant data to support the role of genetics in AF . Considering the broad interplay between various risk factors and genetic tendencies that contribute to AF, as well as heterogeneity of disease pathways (electrical, inflammation, and fibrosis), it is not surprising that the efficacy of AF treatment strategies is variable …”

“…However, advances in sequencing platforms and a decade of data from Genome Wide Association Studies (GWAS) have pushed forward the potential of utilizing genetic variation to predict AF risk, treatments, and outcomes. For AF, GWAS has linked AF risk in multiple large populations with single nucleotide polymorphisms (SNPs) located at 4q25 . In fact, data from these studies illustrate both the power and limitations of GWAS data.…”

“…On one hand, 4q25 AF SNPs are common across populations and therefore may have widespread clinical application for defining AF susceptibility. However, on the other hand, the 4q25 AF SNPs are found in a noncoding region located ∼150 kilobases from any known gene . Thus, similar to other SNPs linked with AF, while clear beacons for disease risk, until recently these variants have not necessarily generated explicit data on disease mechanisms, clinical outcomes, or therapeutic strategies.…”

Genetic Risk Scores for Atrial Fibrillation: Do They Improve Risk Estimation?

“…However, with advances in next generation sequencing increasingly uncovering the contribution of common genetic variation in susceptibility to the arrhythmia, future studies will likely demonstrate net improvements in AF discrimination; thus allowing genetic risk profiling for AF to be incorporated into routine clinical decision-making. 20 …”