Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France.
Service de Biostatistique-Bioinformatique, plateforme de séquençage à haut débit, Hospices Civils de Lyon, Lyon, France.
Orphanet J Rare Dis. 2020 Sep 22;15(1):254. doi: 10.1186/s13023-020-01533-2.
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.
We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.
The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).
In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传病，其特征为多发性毛细血管扩张，由 ENG（HHT1）、ACVRL1（HHT2）和在较小程度上 MADH4 和 GDF2 种系致病变异引起，这些基因编码参与 TGF-β/BMP9 信号通路的蛋白。HHT 的常见内脏并发症由肺、脑或肝动静脉畸形（HAVMs）引起。内脏受累的严重程度在家族内存在很大的变异性，提示存在修饰基因的作用。本研究的目的是研究 ENG、ACVRL1 以及属于同一生物学通路的其他候选基因在 HAVMs 发生中的潜在作用。
我们从法国 HHT 患者数据库中选择了 354 名患者，这些患者在 ENG 或 ACVRL1 中均有一种致病变异，并接受了肝脏探查。我们首先比较了不同类型变异的分布与 HAVMs 的发生情况。然后，我们对来自 Hap Map 数据库的 51 个 Tag-SNPs 进行了基因分型，这些 SNPs 位于编码 TGF-β/BMP9 通路蛋白的 8 个基因（ACVRL1、ENG、GDF2、MADH4、SMAD1、SMAD5、TGFB1、TGFBR1）中，以及另外两个候选基因（PTPN14 和 ADAM17）中。我们研究了遗传关联与 HAVMs 发生之间的关系。
携带生殖系 ACVRL1 变异的患者比例和女性比例在有 HAVMs 的 HHT 患者中显著更高。在 HHT2 组中，截断变异的患者 HAVMs 更常见。有 6 个 SNPs（ACVRL1 中的 3 个、ENG 中的 1 个、SMAD5 中的 1 个和 ADAM17 中的 1 个）与 HAVMs 显著相关。在多重检验校正后，只有一个仍然显著相关（rs2277383）。
在这项大型关联研究中，我们证实了 ACVRL1 与 HAVMs 的发生之间的强关系。ACVRL1 的常见多态性也可能作为一个修饰因子，独立于致病变异，在 HAVMs 的发生中起作用。
