Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus

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Abstract
Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke(1-3) and several mendelian traits featuring stroke have been described(4,5). The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed(6,7). The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke 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 stroke on Japanese rat diet was used as a phenotype. This study identified 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 atrial natriuretic tic and brain natriuretic factors(11). Our investigation 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 highly 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 encoding atrial and brain natriuretic factor and is blood pressure independent.
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