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
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Roger, V. L. et al. Heart disease and stroke statistics-—2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011).
Flossmann, E., Schulz, U. G. & Rothwell, P. M. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 35, 212–227 (2004).
Goldstein, J. L. & Brown, M. S. Molecular medicine. The cholesterol quartet. Science 292, 1310–1312 (2001).
Reyes, S. et al. Apathy: a major symptom in CADASIL. Neurology 72, 905–910 (2009).
Monet-Leprêtre, M. et al. Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain 132, 1601–1612 (2009).
Tikka, S. et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 132, 933–939 (2009).
Joutel, A. et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 358, 2049–2051 (2001).
Singhal, S., Rich, P. & Markus, H. S. The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. AJNR Am. J. Neuroradiol. 26, 2481–2487 (2005).
Liem, M. K. et al. MRI correlates of cognitive decline in CADASIL: a 7-year follow-up study. Neurology 72, 143–148 (2009).
Hara, K. et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N. Engl. J. Med. 360, 1729–1739 (2009).
Mendioroz, M. et al. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 75, 2033–2035 (2010).
Fellgiebel, A., Müller, M. J. & Ginsberg, L. CNS manifestations of Fabry's disease. Lancet Neurol. 5, 791–795 (2006).
Sims, K., Politei, J., Banikazemi, M. & Lee, P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke 40, 788–794 (2009).
Mehta, A. et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data. Lancet 374, 1986–1996 (2009).
Rolfs, A. et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 366, 1794–1796 (2005).
Wozniak, M. A. et al. Frequency of unrecognized Fabry disease among young European-American and African-American men with first ischemic stroke. Stroke 41, 78–81 (2010).
Baptista, M. V. et al. Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study–screening genetic conditions in Portuguese young stroke patients. Stroke 41, 431–436 (2010).
Brouns, R. et al. Belgian Fabry study: prevalence of Fabry disease in a cohort of 1,000 young patients with cerebrovascular disease. Stroke 41, 863–868 (2010).
Richards, A. et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat. Genet. 39, 1068–1070 (2007).
Mateen, F. J. et al. Evolution of a tumor-like lesion in cerebroretinal vasculopathy and TREX1 mutation. Neurology 75, 1211–1213 (2010).
Kernt, M., Gschwendtner, A., Neubauer, A. S., Dichgans, M. & Haritoglou, C. Effects of intravitreal bevacizumab treatment on proliferative retinopathy in a patient with cerebroretinal vasculopathy. J. Neurol. 257, 1213–1214 (2010).
Desai, D. & Dhanani, H. Sickle cell disease: history and origin. The Internet Journal of Hematology [online] (2004).
Oner, C. et al. Beta S haplotypes in various world populations. Hum. Genet. 89, 99–104 (1992).
Lemos Cardoso, G. & Farias Guerreiro, J. African gene flow to north Brazil as revealed by HBB*S. gene haplotype analysis. Am. J. Hum. Biol. 18, 93–98 (2006).
Rahimi, Z., Merat, A., Gerard, N., Krishnamoorthy, R. & Nagel, R. L. Implications of the genetic epidemiology of globin haplotypes linked to the sickle cell gene in southern Iran. Hum. Biol. 78, 719–731 (2006).
Ohene-Frempong, K. et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91, 288–294 (1998).
Lee, M. T. et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood 108, 847–852 (2006).
Sebastiani, P., Ramoni, M. F., Nolan, V., Baldwin, C. T. & Steinberg, M. H. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat. Genet. 37, 435–440 (2005).
Taylor VI, J. G. et al. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood 100, 4303–4309 (2002).
Seshadri, S. et al. Parental occurrence of stroke and risk of stroke in their children: the Framingham study. Circulation 121, 1304–1312 (2010).
MacClellan, L. R. et al. Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet. Epidemiol. 30, 602–608 (2006).
Jerrard-Dunne, P., Cloud, G., Hassan, A. & Markus, H. S. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 34, 1364–1369 (2003).
Schulz, U. G., Flossmann, E. & Rothwell, P. M. Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 35, 819–824 (2004).
Meschia, J. F. Addressing the heterogeneity of the ischemic stroke phenotype in human genetics research. Stroke 33, 2770–2774 (2002).
Dichgans, M. & Markus, H. S. Genetic association studies in stroke: methodological issues and proposed standard criteria. Stroke 36, 2027–2031 (2005).
Luke, M. M. et al. Gene variants associated with ischemic stroke: the cardiovascular health study. Stroke 40, 363–368 (2009).
Matarin, M. et al. Candidate gene polymorphisms for ischemic stroke. Stroke 40, 3436–3442 (2009).
Casas, J. P., Hingorani, A. D., Bautista, L. E. & Sharma, P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch. Neurol. 61, 1652–1661 (2004).
Wang, X. et al. A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients. Stroke 40, 683–695 (2009).
Ariyaratnam, R. et al. Genetics of ischaemic stroke among persons of non-European descent: a meta-analysis of eight genes involving approximately 32,500 individuals. PLoS Med. 4, e131 (2007).
Xin, X. Y. et al. Gene polymorphisms and risk of adult early-onset ischemic stroke: a meta-analysis. Thromb. Res. 124, 619–624 (2009).
Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).
Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).
Bevan, S. et al. Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5,200 cases and 6,600 controls. Stroke 39, 1966–1971 (2008).
Zintzaras, E., Rodopoulou, P. & Sakellaridis, N. Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: a HuGE gene-disease association review and meta-analysis. Am. J. Epidemiol. 169, 523–532 (2009).
McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).
Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Samani, N. J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).
Gschwendtner, A. et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann. Neurol. 65, 531–539 (2009).
Gretarsdottir, S. et al. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann. Neurol. 64, 402–409 (2008).
Lemmens, R. et al. The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology. Stroke 41, 1850–1857 (2010).
Gudbjartsson, D. F. et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat. Genet. 41, 876–878 (2009).
Ikram, M. A. et al. Genomewide association studies of stroke. N. Engl. J. Med. 360, 1718–1728 (2009).
International Stroke Genetics Consortium; Wellcome Trust Case–Control Consortium 2. Failure to validate association between 12p13 variants and ischemic stroke. N. Engl. J. Med. 362, 1547–1550 (2010).
Anderson, C. D. et al. The effect of survival bias on case–control genetic association studies of highly lethal diseases. Circ. Cardiovasc. Genet. 4, 188–196 (2011).
Yamada, Y. et al. Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study. Atherosclerosis 207, 144–149 (2009).
Lanktree, M. B., Dichgans, M. & Hegele, R. A. Advances in genomic analysis of stroke: what have we learned and where are we headed? Stroke 41, 825–832 (2010).
Anderson, C. D. et al. Common mitochondrial sequence variants in ischemic stroke. Ann. Neurol. 69, 471–480 (2010).
Chinnery, P. F., Elliott, H. R., Syed, A. & Rothwell, P. M. Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study. Lancet Neurol. 9, 498–503 (2010).
Rosa, A. et al. Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients. BMC Med. Genet. 9, 57 (2008).
Nishigaki, Y. et al. Mitochondrial haplogroup A is a genetic risk factor for atherothrombotic cerebral infarction in Japanese females. Mitochondrion 7, 72–79 (2007).
Benn, M., Schwartz, M., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Mitochondrial haplogroups: ischemic cerebrovascular disease, other diseases, mortality, and longevity in the general population. Circulation 117, 2492–2501 (2008).
Jood, K., Ladenvall, C., Rosengren, A., Blomstrand, C. & Jern, C. Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke. Stroke 36, 1383–1387 (2005).
FDA Announces new boxed warning on Plavix. FDA [online] (2010).
Mega, J. L. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 376, 1312–1319 (2010).
Wallentin, L. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376, 1320–1328 (2010).
Paré, G. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N. Engl. J. Med. 363, 1704–1714 (2010).
Klein, T. E. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360, 753–764 (2009).
Tan, G. M., Wu, E., Lam, Y. Y. & Yan, B. P. Role of warfarin pharmacogenetic testing in clinical practice. Pharmacogenomics 11, 439–448 (2010).
Link, E. et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N. Engl. J. Med. 359, 789–799 (2008).
Voora, D. et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J. Am. Coll. Cardiol. 54, 1609–1616 (2009).
Table of pharmacogenomic biomakers in drug labels. FDA [online] (2011).
Gershon, E. S. & Goldin, L. R. Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies. Acta Psychiatr. Scand. 74, 113–118 (1986).
Dong, C. et al. Genomewide linkage and peakwide association analyses of carotid plaque in Caribbean Hispanics. Stroke 41, 2750–2756 (2010).
Belfer, I. et al. Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen. Int. J. Stroke 5, 145–151 (2010).
Sacco, R. L. et al. Heritability and linkage analysis for carotid intima–media thickness: the Family Study of Stroke Risk and Carotid Atherosclerosis. Stroke 40, 2307–2312 (2009).
O'Donnell, C. et al. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study. BMC Med. Genet. 8 (Suppl. 1), S4 (2007).
Debette, S. & Markus, H. S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341, c3666 (2010).
Carmelli, D. et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 29, 1177–1181 (1998).
Atwood, L. D. et al. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke 35, 1609–1613 (2004).
Turner, S. T. et al. Heritability of leukoaraiosis in hypertensive sibships. Hypertension 43, 483–487 (2004).
Paternoster, L., Chen, W. & Sudlow, C. L. Genetic determinants of white matter hyperintensities on brain scans: a systematic assessment of 19 candidate gene polymorphisms in 46 studies in 19,000 subjects. Stroke 40, 2020–2026 (2009).
Turner, S. T. et al. Genomic susceptibility loci for brain atrophy, ventricular volume, and leukoaraiosis in hypertensive sibships. Arch. Neurol. 66, 847–857 (2009).
Debette, S. et al. Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. Stroke 41, 210–217 (2010).
dbSNP. National Center for Biotechnology In formation [online] (2011).
International HapMap Project. National Center for Biotechnology In formation [online] (2011).
1000 Genomes Project. 1000 Genomes [online] (2011).
Ng, S. B., Nickerson, D. A., Bamshad, M. J. & Shendure, J. Massively parallel sequencing and rare disease. Hum. Mol. Genet. 19, R119–R124 (2010).
The NINDS Stroke Genetics Network (SiGN) study. University of Maryland School of Medicine [online] (2011).
Causative classification system for ischemic stroke (CCS–Stroke Genetics). The General Hospital Corporation [online] (2011).
dbGAP. National Center for Biotechnology In formation [online] (2011).
Genomics and randomized trials network. Collaborative Health Studies Coordinating Center, University of Washington [online] (2011).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2011.80
This article is cited by
-
Genome-Wide Detection of m6A-Associated Genetic Polymorphisms Associated with Ischemic Stroke
Journal of Molecular Neuroscience (2021)
-
The SNPs rs429358 and rs7412 of APOE gene are association with cerebral infarction but not SNPs rs2306283 and rs4149056 of SLCO1B1 gene in southern Chinese Hakka population
Lipids in Health and Disease (2020)
-
Blood Pressure Control and Protection of the Aging Brain
Neurotherapeutics (2019)
-
The β-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score
Scientific Reports (2017)
-
Phosphodiesterase 4D polymorphisms associate with the short-term outcome in ischemic stroke
Scientific Reports (2017)