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

Nature Genetics volume 16, pages 364–367 (1997)Cite this article

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 stroke1–3 and several mendelian traits featuring stroke have been described4,5. 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 analysed6,7. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes8 as well as an increased sensitivity to experimentally induced focal cerebral ischaemia9,10. Rubattu et al.11 performed a genome-wide screen in an F2 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, STIR-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 and brain natriuretic factors11. 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 F2 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 of 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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Authors and Affiliations

  1. Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow, Gil 6NT, UK

    Baxter Jeffs, James S. Clark, Niall H. Anderson, M. Julia Brosnan, John L. Reid & Anna F. Dominiczak

  2. Wellcome Surgical Institute, University of Glasgow, Garscube Estate, Glasgow, G611QH, UK

    Julie Gratton & I. Mhairi Macrae

  3. The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7LD, UK

    Dominique Gauguier

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  1. Baxter Jeffs
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Correspondence to Anna F. Dominiczak.

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Jeffs, B., Clark, J., Anderson, N. et al. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet 16, 364–367 (1997). https://doi.org/10.1038/ng0897-364

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