Abstract
BackgroundHereditary 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.MethodsWe 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.ResultsNone 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).ConclusionWe 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.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFb/BMP9 pathway genes, most commonly ENG (OMIM 131195) or ACVRL1 (ALK1, OMIM 601284)
HHT is characterized by vascular malformations (VM) ranging from small skin and mucosal telangiectases to arteriovenous malformations (AVM) in lung, liver, and brain, which can lead to severe complications including intracranial hemorrhage (ICH) from ruptured brain VM
We investigated whether the four TGFb modifier locus variants previously reported in HHT lung AVM and seven variants from sporadic AVM studies are associated with organ VM and with brain VM ICH in a large cohort of Caucasian HHT patients enrolled by the Brain Vascular Malformation Consortium (BVMC) (Akers et al, 2013)
Summary
Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFb/BMP9 pathway genes, most commonly ENG (OMIM 131195) or ACVRL1 (ALK1, OMIM 601284). HHT is characterized by vascular malformations (VM) ranging from small skin and mucosal telangiectases to arteriovenous malformations (AVM) in lung, liver, and brain, which can lead to severe complications including intracranial hemorrhage (ICH) from ruptured brain VM. We previously showed that the ACVRL1 c.314-35A>G polymorphism, associated with sporadic brain AVM (Pawlikowska et al, 2005; Simon et al, 2006), is associated with VM in HHT, but only among patients with ENG mutations (Pawlikowska et al, 2015). We investigated whether the four TGFb modifier locus variants previously reported in HHT lung AVM and seven variants from sporadic AVM studies are associated with organ VM and with brain VM ICH in a large cohort of Caucasian HHT patients enrolled by the Brain Vascular Malformation Consortium (BVMC) (Akers et al, 2013)
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