TY - JOUR
T1 - 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
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 - Young, William L.
AU - Kim, Helen
AU - Faughnan, Marie E.
AU - Chakinala, Murali
AU - Gossage, James R.
AU - Henderson, Katharine
AU - Iyer, Vivek
AU - Kasthuri, Raj
AU - Krings, Timo
AU - Lin, Doris
AU - Mager, Johannes Jurgen
AU - McWilliams, Justin
AU - McDonald, Jamie
AU - Pollak, Jeffrey
AU - Ratjen, Felix
AU - Swanson, Karen
AU - terBrugge, Karel
AU - Vethanayagam, Dilini
AU - White, Andrew
AU - White, Robert I.
AU - Wilcox, Pearce
N1 - Publisher Copyright:
© 2015 Wiley Periodicals, Inc.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Arteriovenous malformation
KW - Genetic modifier
KW - Hereditary hemorrhagic telangiectasia
KW - Phenotype
KW - Vascular malformation
UR - http://www.scopus.com/inward/record.url?scp=84929952022&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.36936
DO - 10.1002/ajmg.a.36936
M3 - Article
C2 - 25847705
AN - SCOPUS:84929952022
SN - 1552-4825
VL - 167
SP - 1262
EP - 1267
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 6
ER -