gms | German Medical Science

Objective: Brain arteriovenous malformations (AVM) are vascular lesions that shunt arterial blood directly into draining veins without intervening capillaries. AVMs are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular genetic pathomechanisms underlying AVM development. Mutations in the ENG and ACVRL1 genes cause hereditary hemorrhagic telangiectasia (HHT, M. Osler), which is characterized by hereditary AVMs involving different organ systems, including the CNS. Genes of the Notch family control the normal development of vessels and proper arteriovenous specification. Genetically modified mice with constitutively active Notch4 frequently develop brain AVMs. Here we report a genetic association study investigating possible associations between Notch4 gene polymorphisms and formation of AVMs.

Method: Eleven single nucleotide polymorphisms (SNPs) of the Notch4 gene were sequenced in 173 BAVM patients and 200 healthy controls after PCR amplification. Single marker analysis for each SNP was conducted using the Cochran-Armitage trend test. All haplotype combinations involving up to 4 SNPs were also tested for statistical associations with the formation of AVMs.

Results: Single marker analysis revealed no statistically significant associations. There was a trend for an association between the rs3134798 polymorphism and AVM development (p=0,0874). Five haplotypes consisting of 3 to 4 polymorphisms (all located in the EGF like domain of the Notch4 gene) were significantly more frequent (p<1 x 10^-10) in AVM patients than among controls.

Conclusions: Our results suggest Notch4 polymorphisms as possible genetic risk factors for the development of AVMs (and therefore a role for Notch4 in the pathogenesis of the disease).