AbstractBackgroundHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in theENG (HHT1),ACVRL1 (HHT2)and, to a lesser extentMADH4andGDF2, 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 ofENG,ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.MethodsWe selected 354 patients from the French HHT patient database who had one disease causing variant in eitherENGorACVRL1and 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 (PTPN14andADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.ResultsThe proportion of patients with germlineACVRL1variants 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 inACVRL1, 1 inENG, 1 inSMAD5, and 1 inADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).ConclusionsIn this large association study, we confirmed the strong relationship betweenACVRL1and the development of HAVMs. Common polymorphisms ofACVRL1may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.