Pathogenesis and Radiobiology of Brain Arteriovenous Malformations: Implications for Risk Stratification in Natural History and Post-treatment Course

Achal S. Achrol, B.S.; Raphael Guzman, M.D.; Monika Varga, B.S.; John R. Adler, M.D.; Gary K. Steinberg, M.D.; Ph.D.; Steven D. Chang, M.D.


Neurosurg Focus. 2009;26(5):E9 

In This Article

Genetic Considerations

Genetic analyses have the potential to uncover underlying pathogenic mechanisms of BAVM that could enhance our understanding of vascular disease and identify novel targets for therapeutic intervention. Identification of genetic markers such as SNPs could improve the understanding of BAVM physiology and may be useful in the clinical treatment of patients with BAVMs.

It is likely that the growth and clinical behavior of BAVMs are under genetic influences from multiple modifying pathways that control vascular remodeling and vasculogenesis. For example, HHT is an autosomal dominant genetic disorder with a high prevalence of BAVM, representing an interesting example of genetic influences in the development of BAVM.[6,59] Whereas the incidence of sporadic BAVM in the normal population is estimated to be 0.01%, incidence in HHT2 is 1%, and in HHT1 it is 10%, highlighting the fact that genetic dysfunction in HHT represents a "hyper-risk factor" for development of BAVM.[6,59] The gene involved in HHT1 codes for endoglin, an accessory protein of transforming growth factor-β receptor complexes, whereas HHT2 involves the gene for ALK1, a transmembrane kinase.[59] The highly elevated risk of BAVM development among HHT patients suggests that germline variants of genes relating to these pathways could exert influence over risk for development of sporadic BAVMs. In fact, a common polymorphism in ALK1, thought to result in alternative splicing, has been associated with sporadic BAVM susceptibility,[74] suggesting that genetic variation in genes mutated in heritable BAVM syndromes may play a role in sporadic BAVMs. Furthermore, recent evidence suggests that ALK1 is associated with vascular remodeling and arterialization in response to hemodynamic changes,[81] and loss of function of this gene results in loss of distinct arterial and venous boundaries in mice.[83,86]

Consistent with increasing evidence implicating inflammation in the pathophysiology of BAVM,[15,16,17,71] recent studies of promoter polymorphisms in inflammatory cytokine genes have included the following: 1) association of promoter polymorphisms in IL-1β with BAVM susceptibility;[50] 2) association of a promoter polymorphism in IL-6 with clinical presentation of ICH in BAVM and correlation of IL-6 mRNA and protein levels in resected AVM tissue with genotype;[16,75] and 3) association of promoter polymorphisms in tumor necrosis factor-α and apolipoprotein E2 with new ICH after diagnosis[2,73] as well as risk of posttreatment hemorrhage.[1] These results implicate inflammatory cytokines in pathological angiogenesis and AVM formation as well as risk of ICH in patients harboring BAVMs and highlight the role of genetic screening in elucidating biomechanisms of disease.

Future studies involving genetic analyses in BAVM will include the use of GWAS and high-density SNP arrays. This approach was recently applied to the study of intracranial aneurysms to identify genetic variants that showed significant association with intracranial aneurysms, with odds ratios of 1.24-1.36.[7] The GWAS approaches are now being applied in BAVM with the hope of uncovering underlying pathogenic mechanisms in this important disease.


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