A locus mapping to mouse chromosome 7 determines infarct volume in a mouse model of ischemic stroke.

BACKGROUND In a mouse model of focal cerebral ischemia, infarct volume is highly variable and strain dependent, but the natural genetic determinants responsible for this difference remain unknown. To identify genetic determinants regulating ischemic neuronal damage and to dissect apart the role of individual genes and physiological mechanisms in infarction in mice, we performed quantitative trait locus analysis of surgically induced cerebral infarct volume. METHODS AND RESULTS After permanent occlusion of the distal middle cerebral artery, infarct volume was determined for 16 inbred strains of mice, chromosome substitution strains, and for 2 intercross cohorts, F2 (B6xBALB/c) and F2 (B6xSWR/J). Genome-wide linkage analysis was performed for infarct volume as a quantitative trait. Infarct volume varied up to 30-fold between strains, with heritability estimated at 0.88. Overall, 3 quantitative trait locus were identified that modulate infarct volume, with a major locus (Civq1) on chromosome 7 accounting for >50% of the variation, with a combined LOD score of 21.7. Interval-specific single nucleotide polymorphism haplotype analysis for Civq1 results in 12 candidate genes. CONCLUSIONS The extent of ischemic tissue damage after distal middle cerebral artery occlusion in inbred strains of mice is modulated by genetic variation mapping to at least 3 different loci. A single locus on chromosome 7 determines the majority of the observed variation in the trait. This locus seems to be identical to LSq1, a locus conferring limb salvage and reperfusion in a mouse model of hindlimb ischemia. The identification of the genes underlying these loci may uncover novel genetic and physiological pathways that modulate cerebral infarction and provide new targets for therapeutic intervention in ischemic stroke, and possibly other ischemic diseases.