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© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia
Author
Pawlikowska, Ludmila 1   VIAFID ORCID Logo  ; Nelson, Jeffrey 2 ; Guo, Diana E 2 ; McCulloch, Charles E 3 ; Lawton, Michael T 4 ; Kim, Helen 5 ; Faughnan, Marie E 6 

 Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, CA, USA 
 Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA 
 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA 
 Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA 
 Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA 
 Division of Respirology, Department of Medicine and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada 
Pages
350-356
Section
ORIGINAL ARTICLES
Publication year
2018
Publication date
May 2018
Publisher
John Wiley & Sons, Inc.
e-ISSN
23249269
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2057899962
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.