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Genetics and ischaemic stroke
1Department of Clinical Neurosciences, St George's Hospital Medical School, London, UK.
Insights
Genetic factors significantly influence ischaemic stroke, both in rare monogenic forms like CADASIL and common multifactorial cases. Identifying specific gene mutations in complex stroke remains challenging but is advancing with new technologies.
Area of Science:
- Neurology
- Genetics
- Cardiovascular Disease
Background:
- Ischaemic stroke has both monogenic and multifactorial causes.
- Monogenic strokes, like CADASIL (NOTCH3 gene mutations), often present as multisystem disorders.
- The majority of ischaemic strokes are multifactorial, with complex genetic underpinnings.
Purpose of the Study:
- To review the genetics and phenotypes of monogenic stroke.
- To discuss the challenges and approaches in identifying genetic factors in multifactorial ischaemic stroke.
- To explore the potential of new technologies for studying polygenic stroke.
Main Methods:
- Review of existing literature on monogenic and multifactorial stroke genetics.
- Analysis of candidate gene association studies (haemostatic, homocysteine, ACE, eNOS genes).
- Discussion of limitations of current approaches and future technological advancements.
Main Results:
- Monogenic disorders like CADASIL are recognized causes of familial stroke.
- Candidate gene approaches have investigated various polymorphisms with mixed results.
- Identifying individual causative mutations in multifactorial stroke is problematic due to polygenic inheritance and phenotypic heterogeneity.
Conclusions:
- Genetic factors play a crucial role in ischaemic stroke pathogenesis.
- Novel technologies and bioinformatics are essential for understanding polygenic stroke.
- Future research should leverage advanced methods to unravel the genetic complexity of common stroke.
Abstract:
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.