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

Authors

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

Document Type

Article

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.

Medical Subject Headings

Activin Receptors, Type II (genetics); Adult; Aged; Antigens, CD (genetics); Brain (blood supply, metabolism, pathology); Endoglin; Female; Gene Expression; Heterozygote; Humans; Liver (blood supply, metabolism, pathology); Logistic Models; Male; Middle Aged; Mutation; Phenotype; Polymorphism, Single Nucleotide; Receptors, Cell Surface (genetics); Telangiectasia, Hereditary Hemorrhagic (genetics, pathology); Vascular Malformations (genetics, pathology)

Publication Date

4-8-2015

Publication Title

American journal of medical genetics. Part A

E-ISSN

1552-4833

Volume

167

Issue

6

First Page

1262

Last Page

7

PubMed ID

25847705

Digital Object Identifier (DOI)

10.1002/ajmg.a.36936

Recommended Citation

Pawlikowska, Ludmila; Nelson, Jeffrey; Guo, Diana E.; McCulloch, Charles E.; Lawton, Michael T.; Young, William L.; Kim, Helen; and Faughnan, Marie E., "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" (2015). Neurosurgery. 1114.
https://scholar.barrowneuro.org/neurosurgery/1114