Devan (Portugal)

Background Stroke is a complex disease that is affected by multiple genetic and environmental factors. We utilize the variability in inbred mouse strains to evaluate the genetic basis of susceptibility to cerebral infarction. Methods To identify candidate genes that contribute to this variability in susceptibility, we performed a strain survey on 33 inbred strains of mice using a permanent middle cerebral artery occlusion model. Variability in vascular anatomy was determined by examining the circle of Willis in 22 strains of mice. Infarct volume was obtained and a genome-wide association mapping was performed on 118,019 SNPs using efficient mixed-model association (EMMA) to account for population structure and genetic relatedness in inbred mice. Candidate genes from mice were validated in 34 patients with M1 occlusions from the Genes Associated with Stroke Risk and Outcomes Study (GASROS) and the STOP Stroke Study Results Two SNPs reached genome-wide significance (rs32249495 p=2.08x10-7 and rs3694965 p=2.17x10-7) and two were suggestive (rs31924033 5.61x10-6 and rs3677406 9.46x10-6). Thirty-eight genes were identified to be within 500kb of these four SNPs, corresponding to twenty-four orthologous human genes. SNPs associated with the human orthologs were validated in patients with M1 occlusions. Of these, one SNP (rs1944586, p=1.06x10-4) corresponding to the ZBTB7C gene was significant after adjusting for multiple testing. In vitro analysis demonstrated upregulation of ZBTB7C expression in endothelial cells under hypoxic conditions. Conclusion ZBTB7C may be part of a novel genetic pathway that modulates the severity of cerebral infarction and may serve as a new target for therapeutic intervention in cerebral ischemia.

Purpose: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease appears to influence not only risk of ICH, but also the size of the hematoma. As the burden of high blood pressure(BP)-associated alleles is associated with hypertension-related end-organ damage, we sought to determine if this burden influences ICH admission hematoma volume (AHV). Methods: Prospective study undertaken in 441 ICH patients of European ancestry (210 deep and 231 lobar intracranial hematomas). Forty-three single-nucleotide polymorphisms (SNPs) known to be associated with high BP were genotyped in Illumina610-Quad. Single-SNP association analyses with AHV were performed using linear regression. Subsequently, a genetic risk score was calculated as the sum of the products generated by multiplying, at each of the 43 loci, the number risk alleles times the reported effect of that allele on BP. The score was utilized as the independent variable of univariate and multivariate regression models for 2 outcomes: AHV and poor clinical outcome (modified Rankin Scale 3-6). Principal components analysis was utilized to account for population structure. Results: Individually assessed, no single SNP was associated with AHV. In univariate linear regression, the genetic risk score was associated with AHV in all (deep and lobar) and deep locations (Figure 1), but not in lobar hemorrhages. In multivariate regression analyses, each additional standard deviation of the genetic risk score increased mean deep AHV by 21% (or 2.7-milliliter increase, beta=0.21, standard error=0.08, p=0.01) and risk poor clinical outcome by 55% (odds ratio=1.55, 95% confidence interval 1.05-2.28, p=0.03). No significant associations were observed when considering all (deep and lobar) and lobar hemorrhages. Conclusion: In deep ICH, increasing numbers of high BP-related alleles are associated with larger AHV and poor clinical outcome.