Genetics and ischaemic stroke.
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
Hassan
A
A
Department of Clinical Neurosciences, St George's Hospital Medical School, London, UK.
Markus
H S
HS
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020521:Stroke / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*