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Genetic susceptibility to ischemic stroke

Nature Reviews Neurology volume 7, pages 369–378 (2011)Cite this article

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Abstract

Clinicians who treat patients with stroke need to be aware of several single-gene disorders that have ischemic stroke as a major feature, including sickle cell disease, Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and retinal vasculopathy with cerebral leukodystrophy. The reported genome-wide association studies of ischemic stroke and several related phenotypes (for example, ischemic white matter disease) have shown that no single common genetic variant imparts major risk. Larger studies with samples numbering in the thousands are ongoing to identify common variants with smaller effects on risk. Pharmacogenomic studies have uncovered genetic determinants of response to warfarin, statins and clopidogrel. Despite increasing knowledge of stroke genetics, incorporating this new knowledge into clinical practice remains a challenge. The goals of this article are to review common single-gene disorders relevant to ischemic stroke, summarize the status of candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors, and to briefly discuss pharmacogenomics related to stroke treatment.

Key Points

  • Several single-gene disorders, including sickle cell disease, have ischemic stroke as a major feature

  • Single-gene disorders such as Fabry disease are vital to recognize because they have specific treatments beyond standard stroke preventive therapies that reduce morbidity from stroke and other complications of the underlying disease

  • Genome-wide association and linkage studies have revealed no single locus of major effect applying to ischemic stroke

  • A region on chromosome 9p21.3, containing genetic variants known to associate with coronary artery disease, seems to increase the risk of large-vessel atherosclerotic ischemic stroke, independent of its association with myocardial infarction

  • A region on chromosome 4q25 and the zinc finger homeobox 3 (ZFHX3) gene on chromosome 16q22 are associated with risk of both atrial fibrillation and cardioembolic stroke

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Figure 1: Chromosome 9p21.3 and cardiovascular outcomes.

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Acknowledgements

J. F. Meschia, S. S. Rich and B. B. Worrall receive support from the Siblings with Ischemic Stroke Study (National Institute of Neurological Disorders and Stroke [NINDS] grant code R01 NS39987) and the NINDS Stroke Genetics Network. S. S. Rich also receives support from the US National Heart, Lung and Blood Institute Exome Project, and B. B. Worrall receives support from the Genomics and Randomized Trials Network.

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, 32224, FL, USA

    James F. Meschia

  2. Department of Neurology, University of Virginia, 6111 West Complex, Charlottesville, 22908-0717, VA, USA

    Bradford B. Worrall

  3. Department of Public Health Sciences, University of Virginia, 6111 West Complex, Charlottesville, USA, 22908-0717, VA

    Stephen S. Rich

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B. B. Worrall and S. S. Rich researched data for the article and provided substantial contributions to the discussion of content. J. F. Meschia, B. B. Worrall and S. S. Rich contributed equally to writing, reviewing and editing the article.

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Correspondence to James F. Meschia.

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Meschia, J., Worrall, B. & Rich, S. Genetic susceptibility to ischemic stroke. Nat Rev Neurol 7, 369–378 (2011). https://doi.org/10.1038/nrneurol.2011.80

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