title: NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation.
abstract: OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.
authors.affiliation: Department of Neurosurgery.
authors.forename: Daniel
authors.initials: D
authors.lastname: Delev
authors.affiliation: Institute for Experimental Haematology and Transfusion Medicine, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.affiliation: Department of Neurosurgery.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grote
authors.affiliation: Department of Neurosurgery.
authors.forename: Azize
authors.initials: A
authors.lastname: Boström
authors.affiliation: Department of Neurosurgery, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Höllig
authors.affiliation: Department of Neurosurgery.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, University Medical Center, Bonn; and.
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.affiliation: Institute for Experimental Haematology and Transfusion Medicine, and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Department of Neurosurgery.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics*; D020300:Intracranial Hemorrhages / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D000074562:Receptor, Notch4 / Q000235:genetics*; D055815:Young Adult
chemical_list: C106075:NOTCH4 protein, human; D000074562:Receptor, Notch4
keywords: AVM; AVM = arteriovenous malformation; EGF = epidermal growth factor; NOTCH4; SNP = single-nucleotide polymorphism; association study; brain arteriovenous malformation; single-nucleotide polymorphism; vascular disorders