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      Potential Confounding by Intermediate Phenotypes in Studies of the Genetics of Ischaemic Stroke

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          Background: Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. Methods: We performed a systematic review of case-control and cohort studies reporting on FHx<sub>IHD</sub>, FHx<sub>HTN</sub> or FHx<sub>DM</sub> as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. Results: We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHx<sub>IHD</sub> and FHx<sub>HTN</sub> in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHx<sub>IHD</sub> and 4 out of 11 studies for FHx<sub>HTN</sub>. In contrast, FHx<sub>DM</sub> was not associated with stroke. FHx<sub>IHD</sub> was particularly associated with large vessel strokes (OR 1.72, CI 1.3–2.2, p = 0.00004). Conclusions: FHx<sub>IHD</sub> and FHx<sub>HTN</sub> are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.

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          Most cited references 36

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          Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase.

          The proposal that nitric oxide (NO) or its reactant products mediate toxicity in brain remains controversial in part because of the use of nonselective agents that block NO formation in neuronal, glial, and vascular compartments. In mutant mice deficient in neuronal NO synthase (NOS) activity, infarct volumes decreased significantly 24 and 72 hours after middle cerebral artery occlusion, and the neurological deficits were less than those in normal mice. This result could not be accounted for by differences in blood flow or vascular anatomy. However, infarct size in the mutant became larger after endothelial NOS inhibition by nitro-L-arginine administration. Hence, neuronal NO production appears to exacerbate acute ischemic injury, whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal isoform.
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            The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

            We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
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              The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.

              We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

                Author and article information

                Cerebrovasc Dis
                Cerebrovascular Diseases
                S. Karger AG
                January 2005
                14 January 2005
                : 19
                : 1
                : 1-10
                Stroke Prevention Research Unit, University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK
                81905 Cerebrovasc Dis 2005;19:1–10
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 80, Pages: 10
                Review Paper


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