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Mechanisms and treatment of ischaemic stroke—insights from genetic associations

Nature Reviews Neurology volume 10, pages 723–730 (2014)Cite this article

Subjects

Key Points

  • Genome-wide association studies (GWASs) have identified a number of novel genetic variants that are associated with a risk of ischaemic stroke

  • Most genetic variants identified in GWASs of stroke to date are associated with specific pathophysiological subtypes, including large-artery and cardioembolic stroke

  • Associations of specific genes with specific subtypes of stroke provide insight into the different pathophysiological mechanisms involved, which could lead to the development of novel therapeutic approaches

  • Insights into stroke pathophysiology provided by genetic associations suggest the need for evaluation of treatments in different subtypes and for reliable systems to classify subtypes

  • Larger GWAS cohorts and new approaches such as next-generation sequencing will identify more genetic variants associated with ischaemic stroke to further improve understanding of the disease and clinical care

Abstract

The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings.

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Figure 1: Appearance of different consequences of cerebral small-vessel disease in brain images.

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Acknowledgements

H.S.M. is supported by a National Institute for Health Research Senior Investigator award. H.S.M. and S.B. are supported by the Cambridge University Hospital National Institute for Health Research Biomedical Research Centre.

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  1. Department of Neurology, Stroke Research Group, R3, Box 83, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK

    Hugh S. Markus & Steve Bevan

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H.S.M. researched data for the article, and wrote the article. S.B. contributed to review and editing of the manuscript before submission.

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Correspondence to Hugh S. Markus.

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Markus, H., Bevan, S. Mechanisms and treatment of ischaemic stroke—insights from genetic associations. Nat Rev Neurol 10, 723–730 (2014). https://doi.org/10.1038/nrneurol.2014.196

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