Abstract 2921: Genome-wide Association Reveals Sequence Variants on 4q25 that Affect the Risk of Atrial Fibrillation and Stroke

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over eighty, causes significant morbidity, and is an independent predictor of mortality. We have carried out a genome-wide scan using 316,000 SNPs on an Illumina beadchip to genotype a large atrial fibrillation cohort in Iceland. We found two common sequence variants (SNPs) within the same LD block on chromosome 4q25 near the PITX2 gene which increase the risk of AF substantially (by 1.72 and 1.39 per copy, respectively). An even higher risk was observed in individuals with typical atrial flutter. The association was replicated in Swedish, American, and Chinese populations. These variants do not associate with known risk factors for AF and thus provide an independent predictor of risk. The variants have a stronger effect in individuals younger than 80 but the risk in males and females is indistinguishable. As expected, given that AF is the primary cause of cardiogenic stroke, we found significant correlation to cardiogenic stroke in multiple cohorts. We have now followed up this initial study by combining these two variants to define a test to predict the risk of AF and show its characteristics in a meta-analysis of about 4500 AF patients from four European and American Caucasian cohorts. We demonstrate the effect of age on prediction. About 30% of the general population is positive for this test and has an OR of 1.8 for atrial fibrillation in individuals younger than 80. Such a test may be useful in recently diagnosed ischemic stroke and TIA patients to help decide which patients may benefit from ambulatory cardiac monitoring and perhaps provide a higher yield of detection of asymptomatic intermittent AF that is not discovered during the standard 24 to 48 hour monitoring within the hospital. This may be particularly important given that secondary stroke prevention strategies of antiplatelet agents and statins widely used for atherosclerosis-related strokes are much less effective for preventing strokes caused by AF.