The competing continuation of RO1 NS41877 is responsive to PAS-03-092, """"""""Gene Discovery for Complex Neurological and Neurobehavioral Disorders."""""""" Brain arteriovenous malformations (AVM) are of unknown etiology. This project is a unique effort to discover candidate genes associated with a relatively rare but important cause intracranial hemorrhage (ICH) in young adults.
Specific Aim 1 : Are AVMs associated with specific genotypic changes? These case-control studies will find associations of genotypes to AVM, compared to a cohort of normal controls derived from the same clinical catchment area. The general approach will be: (a) search for candidate genes using a combination of biological plausibility, gene databases and inhouse sequencing; (b) test for associations with multivariate statistical models; and (c) when associations are found, perform haplotyping as guided by the findings of the International HapMap Project. We will test the following specific hypotheses that will demonstrate that single nucleotide polymorphisms (SNPs) in the following candidate genes are associated with AVM: (a) Matrix Metalloproteases, which are critical for vascular remodeling and angiogenesis. (b) TGF-beta receptor-related proteins endoglin and ALK-1. HHT is a mendelian disorder caused by mutations in these genes, has a high incidence of brain and pulmonary AVMs; (c) Tie-2/Angiopoietin Tie-2 is mutated in systemic venous malformation syndrome; its ligand Angiopoietin-1 stabilizes and antagonoist Ang-2 destabilize peri-endothelial vascular support elements in angiogenic vasculature.
Specific Aim 2 : Are there AVM characteristics predicted by genotype? We will perform crosssectional studies in our AVM cohort in the candidate genes described as part of Specific Aim 1 will be explored.
In Specific Aim 2 A, we will test the following specific hypotheses that will demonstrate that the SNPs in the candidate gene are associated with the AVM phenotype: (a) VEGF SNPs will be correlated with AVM size; and (b) Nitric Oxide Synthase (NOS) SNPs will be correlated with the co-existence of arterial.
In Specific Aim 2 B, we will confirm plausibility of associations and functional consequences of identified SNPs by interrogation of fresh frozen tissue removed during AVM microsurgical excision for assay of angiogenic signals. We will use the cases with prospective fresh frozen surgical tissue collection (n=100).
Specific Aim 3 : To identify and correct for population stratification. Case-control genetic association studies are susceptible to spurious associations due to population stratification. We will use random and ancestry informative genetic markers (AIMs) to identify and correct for population stratification among Caucasian and Latino populations, respectively (our two largest sub-groups). We will use statistical methods of correction for population stratification (genomic adjustment) to analyze the association between AVMs and a series of candidate genes in case-control analyses.
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