SENSITIVITY TO CEREBRAL ISCHEMIC INSULT IN A RAT MODEL OF STROKE IS DETERMINED BY A SINGLE GENETIC-LOCUS

Ischaemic stroke is a complex disorder caused by a combination of gene tic and environmental factors. clinical and epidemiological studies ha ve provided strong evidence for genetic influences in the development of human stroke(1-3) and several mendelian traits featuring stroke hav e been described(4,5). The genetic analysis of the non-mendelian, comm on ischaemic stroke in humans is hindered by the late onset of the dis ease and the mode of inheritance, which is complex, polygenic and mult ifactorial. An important approach to the study of such polygenic disea ses is the use of appropriate animal models in which individual contri buting factors can be recognized and analysed(6,7). The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stro ke characterized by a high frequency of spontaneous strokes(8) as well as an increased sensitivity to experimentally induced focal cerebral ischaemia(9,10). Rubattu et al.(11) performed a genome-wide screen in an F-2 cross obtained by mating SHRSP and SHR, in which latency to str oke on Japanese rat diet was used as a phenotype. This study identifie d three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atri al natriuretic tic and brain natriuretic factors(11). Our investigatio n was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F-2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highl y significant QTL on rat chromosome 5 with a lod score trf 16.6 which accounts for 67% of the total variance, co-localizes with the genes en coding atrial and brain natriuretic factor and is blood pressure indep endent.