84 (95% CI, 1.54-2.21). Replication

studies using additional samples from Iceland (2,251 cases and 13,238 controls), Sweden (143 cases and 738 controls), the United States (636 cases and 804 controls), and China (333 cases and 2,836 controls) further reinforced the association with rs2200733. The odds ratio for the combined European population was 1.72 while that for the Chinese cohort was 1.42. The haplotype block corresponding to the associated Inhibitors,research,lifescience,medical SNPs does not contain a known gene, therefore the mechanism for this association is currently unknown. The primary genetic suspect has been PITX2, the nearest known gene in the region, which encodes a transcription factor involved in cardiac development. Following identification of this possible association, investigations using animal models have suggested that reduced expression of PITX2 may predispose to an increased vulnerability to AF although the underlying mechanisms remain unclear.63, Inhibitors,research,lifescience,medical 64 16q22 Following identification of the 4q25 locus, two subsequent genome-wide association studies concurrently identified

separate SNPs, rs7193343 and rs2106261, that both localized to an intronic region Inhibitors,research,lifescience,medical within the ZFHX3 gene on chromosome 16q22.65, 66 ZFHX3 encodes a transcription factor whose function in the heart is currently unclear. The ZFHX3 gene has recently been implicated in a vasculitis involving the coronary arteries (Kawasaki disease).67 The association of 16q22 with AF was weaker than 4q25 in subjects of European ancestry and did not originally

replicate in a Chinese population.65 As with the 4q25 Inhibitors,research,lifescience,medical locus, further work is necessary to better appreciate the apparent relationship between these SNPs within16q22 and AF. 1q21 The initial Inhibitors,research,lifescience,medical two common genetic variants linked with AF were identified predominantly in the context of AF associated with structural heart disease. A third GWAS was performed that focused exclusively on lone AF.68 The study involved 1,335 lone AF cases and 12,844 unaffected controls and identified a third common genetic variant that associated with the check details arrhythmia (adjusted odds ratio of 1.56), which was subsequently replicated in two independent lone AF cohorts. The genetic variant, rs13376333, localizes to chromosome 1q21 and is intronic to KCNN3, a calcium-activated potassium channel that is felt to influence atrial repolarization. Summary AF is also the most common cardiac arrhythmia and is associated with increased rates of heart failure, stroke, and death. Despite its clinical impact, current treatment strategies have relatively modest efficacy that is likely driven by our limited understanding of its underlying pathophysiology. Clinical and epidemiological findings have provided unequivocal evidence that the arrhythmia has a substantial heritable component.