Chr4q25 SNPs modulate differential response to AADs in patients with AF In a preliminary study we addressed whether symptomatic response to AAD therapy is modulated by the 3 common AF susceptibility loci on chr4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3). We studied 478 (discovery cohort) and 198 (validation cohort) age and gender matched Caucasian patients in the Vanderbilt AF Registry. Response to AAD therapy was defined as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥ 75% reduction in AF symptoms. Multiple clinical variables (including age, hypertension, lone AF) failed to predict response to AADs. However, a SNP at the 4q25 locus (rs10033464) was significantly associated with successful symptom control (odds ratio [OR] 2.97, 95% confidence interval [CI] 1.42-6.21, P=0.003). Furthermore, individuals who carried the 4q25 SNP responded better to class I vs. class III AADs in both the discovery and validation cohorts. These preliminary findings provide the rationale for our future studies by suggesting that common AF susceptibility variants differentially modify the response to class I vs. class III AADs in patients with frequent symptomatic AF.