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 Brain Vascular Malformation Consortium HHT Investigator Group

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT 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 associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. 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.

Original languageEnglish (US)
Pages (from-to)1262-1267
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Hereditary Hemorrhagic Telangiectasia
Vascular Malformations
Mutation
Arteriovenous Malformations
Lung
Central Nervous System Vascular Malformations
Genes
Phenotype
Telangiectasis
Liver
Heterozygote
Logistic Models
Genotype
Regression Analysis

Keywords

  • Arteriovenous malformation
  • Genetic modifier
  • Hereditary hemorrhagic telangiectasia
  • Phenotype
  • Vascular malformation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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 Brain Vascular Malformation Consortium HHT Investigator Group.

In: American Journal of Medical Genetics, Part A, Vol. 167, No. 6, 01.06.2015, p. 1262-1267.

Research output: Contribution to journalArticle

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title = "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",
abstract = "Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT 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 associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. 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.",
keywords = "Arteriovenous malformation, Genetic modifier, Hereditary hemorrhagic telangiectasia, Phenotype, Vascular malformation",
author = "{the Brain Vascular Malformation Consortium HHT Investigator Group} and Ludmila Pawlikowska and Jeffrey Nelson and Guo, {Diana E.} and Mcculloch, {Charles E.} and Lawton, {Michael T.} and Young, {William L.} and Helen Kim and Faughnan, {Marie E.} and Murali Chakinala and Gossage, {James R} and Katharine Henderson and Vivek Iyer and Raj Kasthuri and Timo Krings and Doris Lin and Mager, {Johannes Jurgen} and Justin McWilliams and Jamie McDonald and Jeffrey Pollak and Felix Ratjen and Karen Swanson and Karel terBrugge and Dilini Vethanayagam and Andrew White and White, {Robert I.} and Pearce Wilcox",
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T1 - 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

AU - the Brain Vascular Malformation Consortium HHT Investigator Group

AU - Pawlikowska, Ludmila

AU - Nelson, Jeffrey

AU - Guo, Diana E.

AU - Mcculloch, Charles E.

AU - Lawton, Michael T.

AU - Young, William L.

AU - Kim, Helen

AU - Faughnan, Marie E.

AU - Chakinala, Murali

AU - Gossage, James R

AU - Henderson, Katharine

AU - Iyer, Vivek

AU - Kasthuri, Raj

AU - Krings, Timo

AU - Lin, Doris

AU - Mager, Johannes Jurgen

AU - McWilliams, Justin

AU - McDonald, Jamie

AU - Pollak, Jeffrey

AU - Ratjen, Felix

AU - Swanson, Karen

AU - terBrugge, Karel

AU - Vethanayagam, Dilini

AU - White, Andrew

AU - White, Robert I.

AU - Wilcox, Pearce

PY - 2015/6/1

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N2 - Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT 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 associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. 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.

AB - Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT 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 associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. 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.

KW - Arteriovenous malformation

KW - Genetic modifier

KW - Hereditary hemorrhagic telangiectasia

KW - Phenotype

KW - Vascular malformation

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JO - American Journal of Medical Genetics, Part A

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