Common risk variants for atrial fibrillation on chromosomes 4q25 and 16q22 associate with non-cardiogenic stroke suggesting that AF is a greater cause of stroke than previously recognized

Abstract

Background: Multiple genome-wide association studies, including our own, have discovered multiple common single nucleotide polymorphism (SNP) variants on chromosome 4q25 near the PITX2 gene and 16q22 near ZHFX3 that widely replicate in numerous independent populations as risk factors for atrial fibrillation (AF) and which are independent of conventional risk factors for AF including family history. These variants have been replicated in about 9000 AF patients and 40,000 controls. These genes are expressed in atrial muscle and their gene products are transcriptional activators that may interact within the same complex. Hypothesis: We assessed the hypothesis that common genetic risk factors for AF were risk factors for cardiogenic stroke. Methods: Three SNPs were used to genotype 5 large case-control studies of ischemic stroke patients, totalling 6235 cases and 39,898 controls. They included two SNPs which represent 2 independent association signals on 4q25, rs2200733 and rs10033464, and rs7193343 on 16q22. Results: rs2200733 and rs7193343 showed highly significant association to ischemic stroke with per allele OR of 1.26 and 1.11, respectively. All three SNPs showed significantly greater association to cardioembolic stroke with per allele OR ranging from 1.22 to 1.52 (rs2200733: OR=1.52, P=5.8x10-12; rs10033464: OR=1.27, P=6.1x10-4; rs7193343: OR 1.22, P= 0.00021). Combining the risks from 3 markers using a multiplicative model is supported by the data; the upper ten-percentile of risk for cardiogenic stroke ranged from 2.0 to 3.5 fold. Interestingly, rs2200733 also showed significant association to ischemic stroke after subtracting patients with known cardiogenic stroke. It also showed association to cryptogenic stroke and large vessel stroke, although with lower magnitude of risk, supporting the notion that a substantial number of patients in these subcategories are misdiagnosed and really have intermittent AF that is notdiagnosed during the standard stroke workup. Conclusion: We have discovered that multiple common variants previously shown to associate with AF, significantly associate with cardiogenic stroke. Given the association to cryptogenic stroke, the genetic markers may be useful to define patients who may benefit from extra cardiac monitoring for intermittent AF. Clinical utility studies are needed to show that extra monitoring in patients with higher genetic risk substantially improves the diagnostic sensitivity of cardiogenic stroke.