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

Am J Med Genet A. 2015 Jun;167(6):1262-7. doi: 10.1002/ajmg.a.36936. Epub 2015 Apr 2.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • ACVRL1 protein, human
  • Activin Receptors, Type II