Open AccessAssociation of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia
Author(s) -
Pawlikowska Ludmila,
Nelson Jeffrey,
Guo Diana E.,
McCulloch Charles E.,
Lawton Michael T.,
Kim Helen,
Faughnan Marie E.
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.377
Subject(s) - telangiectasia , medicine , arteriovenous malformation , phenotype , intracerebral hemorrhage , acvrl1 , pathology , lung , vascular malformation , endoglin , candidate gene , intracranial arteriovenous malformations , gene , biology , genetics , subarachnoid hemorrhage , cerebral angiography , stem cell , radiology , angiography , cd34
Background Hereditary hemorrhagic telangiectasia ( HHT ) is caused by mutations in TGF β/ BMP 9 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 ( PTPN 14 rs2936018, USH 2A rs700024, ADAM 17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH ( APOE ε2, ANGPTL 4 rs11672433, EPHB 4 rs314308, IL 6 rs1800795, IL 1B rs1143627, ITGB 8 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 USH 2A 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 .