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

Authors

Ludmila Pawlikowska, Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Jeffrey Nelson, Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Diana E. Guo, Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Charles E. McCulloch, Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
Michael T. Lawton, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Helen Kim, Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Marie E. Faughnan, Division of Respirology, Department of Medicine and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.

Document Type

Article

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.

Medical Subject Headings

Adult; Aged; Brain (blood supply); Central Nervous System Vascular Malformations (complications); Female; Genetic Association Studies (methods); Genotype; Humans; Intracranial Arteriovenous Malformations (complications); Intracranial Hemorrhages (complications); Liver (blood supply); Lung (blood supply); Male; Middle Aged; Mutation; Phenotype; Telangiectasia, Hereditary Hemorrhagic (complications, genetics, physiopathology); Transforming Growth Factor beta (genetics, metabolism); Vascular Malformations (complications)

Publication Date

6-23-2018

Publication Title

Molecular genetics & genomic medicine

E-ISSN

2324-9269

Volume

6

Issue

3

First Page

350

Last Page

356

PubMed ID

29932521

Digital Object Identifier (DOI)

10.1002/mgg3.377

Recommended Citation

Pawlikowska, Ludmila; Nelson, Jeffrey; Guo, Diana E.; McCulloch, Charles E.; Lawton, Michael T.; Kim, Helen; and Faughnan, Marie E., "Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia" (2018). Neurosurgery. 1297.
https://scholar.barrowneuro.org/neurosurgery/1297