The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations.
The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations.
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DOI：
10.1002/ajmg.a.36936
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发表时间：
2015-06
影响因子：
2
通讯作者：
Faughnan, Marie E.
中科院分区：
文献类型：
--
作者：
Pawlikowska, Ludmila;Nelson, Jeffrey;Guo, Diana E.;McCulloch, Charles E.;Lawton, Michael T.;Young, William L.;Kim, Helen;Faughnan, Marie E.
关键词：
遗传性出血性毛细血管扩张 (HHT) 的特征是存在血管畸形 (VM)，由 TGFβ/BMP9 通路基因（最常见的是 ENG 或 AVRL1）突变引起。 HHT 患者具有与皮肤和粘膜毛细血管扩张以及器官 VM 相关的多种表型，包括动静脉畸形 (AVM)。 HHT 的临床异质性表明遗传修饰效应的潜在作用。我们假设之前与散发性脑 AVM 相关的常见多态性 AVRL1 c.314-35A>G 和 ENG c.207G>A 也与 HHT 中的器官 VM 相关。我们对脑血管畸形联盟招募的 716 名 HHT 患者进行了 AVRL1 c.314-35A>G 和 ENG c.207G>A 的基因分型，并通过按 HHT 突变分层的多变量逻辑回归分析，评估了基因型与任何器官 VM 存在的关联，特别是与脑 VM、肝脏 VM 和肺 AVM 的关联。在所有 HHT 患者中，这两种多态性均与任何器官 VM 的存在没有显着相关性。 AVRL1 c.314-35A>G 显示出与肺 AVM 相关的趋势（OR=1.48，p=0.062）。 AVRL1 c.314-35A>G 与伴有 ENG 的 HHT 患者中的任何 VM 显着相关（OR=2.66，p=0.022），但与 AVRL1（OR=0.79，p=0.52）突变无关。 AVRL1 c.314-35A>G 也与 ENG 突变携带者中的肺 AVM 和肝 VM 显着相关。 ENG c.207G>A 与任何 VM 表型之间没有显着关联。这些结果表明，除突变基因外，HHT 基因中常见的多态性调节 HHT 疾病的表型严重程度，特别是器官 VM 的存在。
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse phenotypes related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a potential role for genetic modifier effects. We hypothesized that the common polymorphisms ACVRL1 c.314-35A>G and ENG c.207G>A, previously associated with sporadic brain AVM, are also associated with organ VM in HHT. We genotyped ACVRL1 c.314-35A>G and ENG c.207G>A in 716 patients with HHT recruited by the Brain Vascular Malformation Consortium and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR=1.48, p=0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR=2.66, p=0.022), but not ACVRL1 (OR=0.79, p=0.52) mutations. ACVRL1 c.314-35A>G was also significantly associated with pulmonary AVM and liver VM among ENG mutation carriers. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM.
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DOI：
10.1161/circgenetics.113.000023
发表时间：
2013-08
期刊：
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影响因子：
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