A Common Connexion Between Gap Junctions, Single Nucleotide Polymorphisms, and Atrial Fibrillation?

Abstract

Atrial fibrillation (AF) is a common arrhythmia associated with substantial morbidity. In younger individuals without structural heart disease, the arrhythmia is commonly referred to as “lone” AF. It is now apparent that a widespread heritable basis for AF exists, the heritability might be greater among those with lone AF as compared with older individuals or those with structural heart disease. In 1997, Brugada et al. mapped a genetic locus for AF to the long arm of chromosome 10 in a family with early onset AF and no substantial structural heart disease. Since that report, investigators have used a combination of candidate gene screening and functional characterization to identify a variety of mutations, often in ion channels, that underlie monogenic forms of AF. More recently, genome-wide association studies have been used to map 9 susceptibility loci associated with AF in case-control and population-based cohort samples. Despite their rarity, the discovery of mutations underlying monogenic AF has provided important insights into AF pathophysiology. For example, most identified mutations in potassium channels are expected to shorten the atrial action potential and thereby predispose to re-entry, supporting a commonly accepted mechanism of AF. Considering evidence that alterations in ion channels can predispose to AF, genes encoding gap junction proteins have become plausible candidates for AF susceptibility. Gap junctions are responsible for electrical coupling of cells. Specifically, connexin-40 has been investigated as a potential candidate because of its selective expression in the atria and presence in cardiac conduction tissue. Connexin-40 forms atrial gap junctions together with connexin-43. Indeed, genetic variation in GJA5, which encodes connexin-40, has been associated with AF in several studies. Invoked mechanisms that might underlie the association include impaired cellular transport of