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Abstract

Stroke is a complex disorder with a poorly understood multifactorial and polygenic aetiology. We used the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genome-wide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder) segregated. We identified three major quantitative trait loci, STR1-3, with lod scores of 7.4, 4.7 and 3.0, respectively, that account for 28% of the overall phenotypic variance. STR2 colocalizes with the genes encoding atrial and brain natriuretic factor, peptides with important vasoactive properties. Our results demonstrate the existence of primary, blood pressure-independent genetic factors predisposing to a complex form of stroke.

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Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial.

Marc Jacobs, H Iso, D N Wentworth … (1989)

We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).

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Construction of multilocus genetic linkage maps in humans.

E. Lander, P. Green (1987)

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12.

J Weissenbach, Juan Carrique-Mas, E. Tournier … (1993)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.

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PubMed ID:: 8696337

DOI:: 10.1038/ng0896-429

ScienceOpen disciplines: Chemistry

Keywords: Animals,Blood Pressure,Cerebrovascular Disorders,genetics,Chromosome Mapping,methods,Disease Models, Animal,Genetic Linkage,Humans,Phenotype,Rats,Rats, Inbred SHR

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ScienceOpen disciplines: Chemistry

Keywords: Animals, Blood Pressure, Cerebrovascular Disorders, genetics, Chromosome Mapping, methods, Disease Models, Animal, Genetic Linkage, Humans, Phenotype, Rats, Rats, Inbred SHR

Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.

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Most cited references 29

Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial.

Construction of multilocus genetic linkage maps in humans.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12.

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