背景:ZFHX3基因(16q22)是与心房颤动(AF)密切相关的第二大基因,与炎症和纤维化有关。我们假设ZFHX3与肺外静脉(PV)触发相关,左心房(LA)结构重构,房颤导管消融术(AFCA)的不良心律结果。方法:我们纳入了1,782例接受从头AFCA的患者(73.5%男性,59.4±10.8岁,65.9%阵发性房颤)和全基因组关联研究,并将其分为发现(n=891)和复制队列(n=891)。所有纳入的患者均接受了异丙肾上腺素激发试验和LA电压映射。我们分析了ZFHX3,额外的PV触发因素,和节奏结果。结果:在ZFHX3的14个单核苷酸多态性(SNP)中,rs13336412,rs61208973,rs2106259,rs12927436和rs1858801与额外的PV触发因素有关。在整个患者组中,肺静脉外触发因素与ZFHX3多基因风险评分(PRS)独立相关(OR1.65[1.22-2.22],p=0.001,型号1)和低LA电压(OR0.74[0.56-0.97],p=0.029,型号2)。随访49.9±40.3个月,有肺静脉外触发因素的患者房颤的临床复发率明显更高(Log-rankp<0.001,HR1.89[1.49-2.39],p<0.001,模型1),大LA维度(对数秩p<0.001,HR1.03[1.01-1.05],p=0.002,模型2),和低LA电压(对数秩p<0.001,HR0.73[0.61-0.86],p<0.001,模型2),但不是ZFHX3PRS(对数秩p=0.819)。结论:肺静脉外触发因素与ZFHX3基因多态性和获得性LA重塑均有显著关联。尽管肺静脉外触发因素是AFCA后房颤复发的独立预测因素,所研究的ZFHX3中房颤风险SNPs内含子与房颤复发无关.
Background: The
ZFHX3 gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that
ZFHX3 is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA). Methods: We included 1,782 patients who underwent a de novo AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery (n = 891) and replication cohorts (n = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the
ZFHX3, extra-PV trigger-related factors, and rhythm outcomes. Result: Among 14 single-nucleotide polymorphisms (SNPs) of
ZFHX3, rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the
ZFHX3 polygenic risk score (PRS) (OR 1.65 [1.22-2.22], p = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56-0.97], p = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank p < 0.001, HR 1.89 [1.49-2.39], p < 0.001, model 1), large LA dimensions (Log-rank p < 0.001, HR 1.03 [1.01-1.05], p = 0.002, model 2), and low LA voltages (Log-rank p < 0.001, HR 0.73 [0.61-0.86], p < 0.001, model 2) but not the ZFHX3 PRS (Log-rank p = 0.819). Conclusion: The extra-PV triggers had significant associations with both ZFHX3 genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in ZFHX3 were not associated with AF recurrence.