Mints Yuliya, Yarmohammadi Hirad, Khurram Irfan M, Hoyt Hana, Hansford Rozann, Zimmerman Stefan L, Steinberg Steven J, Judge Daniel P, Tomaselli Gordon F, Calkins Hugh, Zipunnikov Vadim, Nazarian Saman
Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
Clin Med Insights Cardiol. 2015 May 13;9:39-45. doi: 10.4137/CMC.S21712. eCollection 2015.
Recent studies have shown that several genetic variants near the PITX2 locus on chromosome 4q25 are associated with atrial fibrillation (AF). However, the mechanism that mediates this association remains unclear. Basic murine studies suggest that reduced PITX2 expression is associated with left atrial dilatation. We sought to examine the association between single nucleotide polymorphisms (SNPs) near PITX2 and left atrial size in patients with AF.
We prospectively enrolled 96 consecutive patients (mean age 60 ± 10 years, 72% male) with drug-resistant AF (57% paroxysmal, 38% persistent, and 5% long-standing persistent) who underwent catheter ablation. Following DNA extraction from blood obtained pre-operatively, SNPs rs10033464 and rs2200733 were genotyped using the Sequenom MassARRAY. Left atrial volume (LAV) was determined using three-dimensional imaging (CT or MRI prior to first ablation) and by investigators blinded to genotype results.
The minor allele frequencies at SNPs rs10033464 and rs2200733 were 0.14 and 0.25, respectively. Using multivariable linear regression, homozygosity for the minor allele at rs10033464 (recessive model) was independently associated with larger LAV (P = 0.002) after adjustment for age, gender, BMI, height, type, and duration of AF, left ventricular ejection fraction, history of hypertension, valve disease, and antiarrhythmic drug use. The strength of the association was reconfirmed in a bootstrap study with 1000 resamplings. In contrast, no association was found between rs2200733 variant alleles and LAV.
SNP rs10033464 near the PITX2 locus on 4q25 is associated with LAV. Left atrial dilatation may mediate the association of common variants at 4q25 with AF.
近期研究表明，4号染色体4q25上PITX2基因座附近的几个基因变异与心房颤动（AF）相关。然而，介导这种关联的机制仍不清楚。基础小鼠研究表明，PITX2表达降低与左心房扩张有关。我们试图研究AF患者中PITX2附近单核苷酸多态性（SNP）与左心房大小之间的关联。
我们前瞻性纳入了96例连续的耐药性AF患者（平均年龄60±10岁，72%为男性），这些患者接受了导管消融治疗（57%为阵发性，38%为持续性，5%为长期持续性）。术前从血液中提取DNA后，使用Sequenom MassARRAY对SNP rs10033464和rs2200733进行基因分型。使用三维成像（首次消融前的CT或MRI）并由对基因型结果不知情的研究人员确定左心房容积（LAV）。
SNP rs10033464和rs2200733的次要等位基因频率分别为0.14和0.25。使用多变量线性回归，在校正年龄、性别、BMI、身高、AF类型和持续时间、左心室射血分数、高血压病史、瓣膜病和抗心律失常药物使用情况后，rs10033464次要等位基因的纯合性（隐性模型）与更大的LAV独立相关（P = 0.002）。在一项进行了1000次重采样的自抽样研究中再次证实了这种关联的强度。相比之下，未发现rs2200733变异等位基因与LAV之间存在关联。
4q25上PITX2基因座附近的SNP rs10033464与LAV相关。左心房扩张可能介导4q25上常见变异与AF之间的关联。
