Abstract WP258: ZBTB7C Is Associated With Severity Of Infarction In Cerebral Ischemia

Abstract

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.