Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia.
ACVRL1
HHT, Rendu-Osler
Hepatic arteriovenous malformation
Modifier gene
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
22 09 2020
22 09 2020
Historique:
received:
08
04
2020
accepted:
07
09
2020
entrez:
23
9
2020
pubmed:
24
9
2020
medline:
19
5
2021
Statut:
epublish
Résumé
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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
Identifiants
pubmed: 32962750
doi: 10.1186/s13023-020-01533-2
pii: 10.1186/s13023-020-01533-2
pmc: PMC7507685
doi:
Substances chimiques
Endoglin
0
ACVRL1 protein, human
EC 2.7.11.30
Activin Receptors, Type II
EC 2.7.11.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
254Références
Front Genet. 2015 Jan 26;6:1
pubmed: 25674101
J Anim Sci. 2010 Feb;88(2):497-504
pubmed: 19820058
Circulation. 2017 Sep 12;136(11):1037-1048
pubmed: 28687708
Am J Hum Genet. 2003 Dec;73(6):1240-9
pubmed: 14639529
Blood. 2007 Mar 1;109(5):1953-61
pubmed: 17068149
Mol Genet Genomic Med. 2018 May;6(3):350-356
pubmed: 29932521
Hum Mutat. 2005 Mar;25(3):320
pubmed: 15712270
Bioinformatics. 2005 Jan 15;21(2):263-5
pubmed: 15297300
Am J Med Genet A. 2006 Mar 1;140(5):463-70
pubmed: 16470787
Front Genet. 2015 Mar 12;6:67
pubmed: 25815003
Am J Hum Genet. 2013 Sep 5;93(3):530-7
pubmed: 23972370
Proc Natl Acad Sci U S A. 2014 May 27;111(21):7723-8
pubmed: 24812125
Nat Commun. 2012 Jan 10;3:616
pubmed: 22233626
Hepatology. 2008 Nov;48(5):1570-6
pubmed: 18972447
Genet Med. 2007 Jan;9(1):14-22
pubmed: 17224686
Nat Genet. 1994 Dec;8(4):345-51
pubmed: 7894484
Eur J Hum Genet. 2008 Jun;16(6):742-9
pubmed: 18285823
Acta Otolaryngol. 2012 Jan;132(1):86-9
pubmed: 22185213
Semin Liver Dis. 2008 Aug;28(3):247-58
pubmed: 18814078
Hum Mol Genet. 2003 Jul 1;12(13):1579-89
pubmed: 12812985
Hum Mutat. 2006 Jun;27(6):598
pubmed: 16705692
Am J Med Genet A. 2015 Jun;167(6):1262-7
pubmed: 25847705
J Cell Physiol. 2005 Aug;204(2):574-84
pubmed: 15702480
Nat Genet. 1996 Jun;13(2):189-95
pubmed: 8640225
J Med Genet. 2003 Aug;40(8):585-90
pubmed: 12920067
Lancet. 2004 Mar 13;363(9412):852-9
pubmed: 15031030
Am J Med Genet. 1989 Mar;32(3):291-7
pubmed: 2729347
J Med Genet. 2006 Apr;43(4):371-7
pubmed: 16155196
Orphanet J Rare Dis. 2020 Mar 2;15(1):63
pubmed: 32122373
JAMA. 2012 Mar 7;307(9):948-55
pubmed: 22396517
Clin Otolaryngol Allied Sci. 2000 Dec;25(6):570-6
pubmed: 11123171