Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia

the Brain Vascular Malformation Consortium HHT Investigator Group

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium. Methods: We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering. Results: None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13–6.80, p =.026). Conclusion: We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.

Original languageEnglish (US)
Pages (from-to)350-356
Number of pages7
JournalMolecular Genetics and Genomic Medicine
Volume6
Issue number3
DOIs
StatePublished - May 1 2018

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Hereditary Hemorrhagic Telangiectasia
Vascular Malformations
Intracranial Hemorrhages
Arteriovenous Malformations
Central Nervous System Vascular Malformations
Lung
Intracranial Arteriovenous Malformations
Brain
Phenotype
Liver
Knockout Mice
Genes
Cluster Analysis
Interleukin-6
Logistic Models
Genotype
Mutation

Keywords

  • arteriovenous malformation
  • genetic modifiers
  • hereditary hemorrhagic telangiectasia
  • intracerebral hemorrhage
  • vascular malformation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia. / the Brain Vascular Malformation Consortium HHT Investigator Group.

In: Molecular Genetics and Genomic Medicine, Vol. 6, No. 3, 01.05.2018, p. 350-356.

Research output: Contribution to journalArticle

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title = "Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia",
abstract = "Background: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium. Methods: We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering. Results: None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95{\%} CI = 1.13–6.80, p =.026). Conclusion: We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.",
keywords = "arteriovenous malformation, genetic modifiers, hereditary hemorrhagic telangiectasia, intracerebral hemorrhage, 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 Helen Kim and Faughnan, {Marie E.} and Murali Chakinala and Marianne Clancy and Gossage, {James R} and Katharine Henderson and Hetts, {Steven W.} and Vivek Iyer and Raj Kasthuri and Timo Krings and Doris Lin and Mager, {Johannes Jurgen} and Douglas Marchuk and McWilliams, {Justin P.} and Jamie McDonald and Jeffrey Pollak and Felix Ratjen and Karen Swanson and Karel terBrugge and Dilini Vethanayagam and Andrew White and Pearce Wilcox",
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T1 - Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia

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 - Kim, Helen

AU - Faughnan, Marie E.

AU - Chakinala, Murali

AU - Clancy, Marianne

AU - Gossage, James R

AU - Henderson, Katharine

AU - Hetts, Steven W.

AU - Iyer, Vivek

AU - Kasthuri, Raj

AU - Krings, Timo

AU - Lin, Doris

AU - Mager, Johannes Jurgen

AU - Marchuk, Douglas

AU - McWilliams, Justin P.

AU - McDonald, Jamie

AU - Pollak, Jeffrey

AU - Ratjen, Felix

AU - Swanson, Karen

AU - terBrugge, Karel

AU - Vethanayagam, Dilini

AU - White, Andrew

AU - Wilcox, Pearce

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Background: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium. Methods: We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering. Results: None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13–6.80, p =.026). Conclusion: We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.

AB - Background: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium. Methods: We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering. Results: None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13–6.80, p =.026). Conclusion: We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.

KW - arteriovenous malformation

KW - genetic modifiers

KW - hereditary hemorrhagic telangiectasia

KW - intracerebral hemorrhage

KW - vascular malformation

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DO - 10.1002/mgg3.377

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