A Functional Polymorphism C-509T in TGFβ-1 Promoter Contributes to Susceptibility and Prognosis of Lone Atrial Fibrillation in Chinese Population

Transforming growth factor-β1 (TGF-β1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). But the involved genetic mechanism is unknown. Herein, the TGF-β1 C-509T polymorphism (rs1800469) was genotyped in a case-control study of 840 patients and 845 controls in Chinese population to explore the association between the polymorphism and susceptibility and prognosis of lone AF. As a result, the CT and/or TT genotypes had an increased lone AF risk [adjusted odds ratio (OR) = 1.50 for CT, OR = 3.72 for TT, and OR = 2.15 for CT/TT], compared with the TGF-β1CC genotype. Moreover, patients carrying CT/TT genotypes showed a higher possibility of AF recurrence after catheter ablation, compared with patients carrying CC genotype. In a genotype-phenotype correlation analysis using 24 normal left atrial appendage samples, increasing gradients of atrial TGF-β1 expression levels positively correlated with atrial collagen volume fraction were identified in samples with CC, CT and TT genotypes. The in vitro luciferase assays also showed a higher luciferase activity of the -509T allele than that of the -509C allele. In conclusion, the TGF-β1 C-509T polymorphism is involved in the etiology of lone AF and thus may be a marker for genetic susceptibility to lone AF and predicting prognosis after catheter ablation in Chinese populations. Therefore, we provide new information about treatment strategies and our understanding of TGF-β1 in AF.转化生长因子-β1（Transforming growth factor-β1, TGF-β1）是心房纤维化与心房颤动（atrial fibrillation, AF）的重要介导因子，但其相关遗传机制尚未阐明。本研究针对中国人群开展病例对照研究（case-control study），对840例孤立性房颤（lone AF）患者与845例对照者的转化生长因子-β1 C-509T多态性（rs1800469）进行基因分型，以探究该多态性与孤立性房颤易感性及预后的关联。结果显示，与转化生长因子-β1 CC基因型相比，CT基因型、TT基因型以及CT/TT联合基因型可显著升高孤立性房颤的发病风险[校正后比值比（adjusted odds ratio, OR）：CT型为1.50，TT型为3.72，CT/TT联合型为2.15]。此外，携带CT/TT基因型的患者在接受导管消融术（catheter ablation）后，房颤复发的概率显著高于携带CC基因型的患者。通过对24例正常左心耳（left atrial appendage）样本开展基因型-表型关联分析（genotype-phenotype correlation analysis），本研究发现CC、CT、TT基因型样本的心房TGF-β1表达水平呈递增梯度，且与心房胶原容积分数（collagen volume fraction）呈显著正相关。体外荧光素酶实验（luciferase assays）亦证实，-509T等位基因（allele）的荧光素酶活性高于-509C等位基因。综上，转化生长因子-β1 C-509T多态性参与孤立性房颤的病因学（etiology）过程，可作为中国人群孤立性房颤遗传易感性（genetic susceptibility）以及导管消融术后预后预测的分子标志物。本研究为房颤领域的治疗策略制定及转化生长因子-β1的相关认知提供了新的理论依据。