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Advances in Stroke

2013; Lippincott Williams & Wilkins; Volume: 44; Issue: 2 Linguagem: Inglês

10.1161/strokeaha.111.000480

1524-4628

James F. Meschia, Elisabeth Tournier‐Lasserve,

Cerebrovascular and genetic disorders

HomeStrokeVol. 44, No. 2Advances in Stroke Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBAdvances in StrokeGenetics 2012 James F. Meschia, MD and Elizabeth Tournier-Lasserve, MD James F. MeschiaJames F. Meschia From the Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); and Service de Genetique Neuro-Vasculaire, AP-HP, Groupe Hospitalier Lariboisiere-Fernand-Widal and INSERM UMR-S740, Paris, France (E.T.-L.). and Elizabeth Tournier-LasserveElizabeth Tournier-Lasserve From the Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); and Service de Genetique Neuro-Vasculaire, AP-HP, Groupe Hospitalier Lariboisiere-Fernand-Widal and INSERM UMR-S740, Paris, France (E.T.-L.). Originally published15 Jan 2013https://doi.org/10.1161/STROKEAHA.111.000480Stroke. 2013;44:309–310Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 The field of stroke genetics continues to make substantive advances. Large-scale partnerships have led to meta-analyses in ischemic and hemorrhagic stroke, which are yielding reproducible genetic risk factors. Most ischemic stroke risk factors seem to be specific to type, for example, large-vessel stroke. Progress is being made in understanding the pathophysiology of single-gene stroke syndromes. Genetics is also being used to potentially advance pharmacotherapeutics.In the genome-wide association study (GWAS) era, several themes are emerging. First, heritability seems to vary by ischemic stroke subtype. Using complex trait analysis on a GWAS data set of >3000 individuals, Bevan et al1 found a 37.9% heritability for ischemic stroke overall, but the heritability varied widely by subtype from a high of 40.3% for large-vessel stroke to a low of 16.1% for small-vessel stroke.1 Second, genetic risk factors seem to be subtype-selective. Third, GWAS have yielded more reliable discoveries than candidate gene studies uninformed by GWAS. In the previously cited study by Bevan,1 no candidate gene previously reported as associated with ischemic stroke could be replicated using GWAS data, but 3 loci from related cardiovascular GWAS were significant even after rigorous correction for multiple comparisons.In the area of ischemic stroke genetics, a partnership between the International Stroke Genetics Consortium and the Wellcome Trust Case Control Consortium 2, which included GWAS data from 5859 cases and 6281 controls, replicated associations of PITX2 and ZFHX3 with cardioembolic stroke and of a locus 9p21 with large-vessel stroke. The partnership also led to the discovery of an association between large-vessel stroke and histone deacetylase 9 (HDAC9).2 The subsequent METASTROKE collaboration, which performed a meta-analysis of data from 12 389 ischemic stroke cases and 62 004 controls of European descent, confirmed genome-wide significant associations of PITX2 and ZFHX3 with cardioembolic stroke and HDAC9 with large-vessel ischemic stroke.3 The associations remained significant when the meta-analysis was repeated, excluding populations that contributed to the original discoveries. In addition, single-nucleotide polymorphisms (SNPs) in an intergenic region of the 6p21.1 locus were found to be associated with large artery atherosclerotic stroke.4 There are now several loci associated with large-vessel stroke discovered by GWAS (Table).Table. Genes and Loci Associated With Large-vessel Ischemic StrokeGene or LocusSNPOdds Ratio9p21.3rs23832071.17HDAC9rs119840411.426p21.1rs5566211.21LPArs10455872 and rs3798220, combined in a risk score1.27PHACTR1rs125264530.94*HDAC9 indicates histone deacetylase 9; LPA, apolipoprotein A; PHACTR1, phosphatase and actin regulator 1; and SNP, single-nucleotide polymorphism.*Personal communication from Steve Bevan.Using a 2-SNP risk score, investigators found an association between the apolipoprotein A (LPA) gene and large-vessel ischemic stroke; however, no such association was found for small-vessel stroke or venous thromboembolism, suggesting that LPA variation and the consequent rise in blood lipoprotein A levels act through an atherosclerotic rather than a thrombotic mechanism.5 Testing loci from related cardiovascular phenotypes, investigators found an association of PHACTR1 with large-vessel stroke.1None of the studies identifying risk factors for large-vessel ischemic stroke included a control group of subjects with known asymptomatic carotid stenosis. From a clinical perspective, it would be interesting to know whether a genetic risk score could be created to stage risk of future ischemic stroke in patients with asymptomatic stenosis. Such a score, either in isolation or, more likely, in combination with clinical and radiographic variables could be used to select the most appropriate patients for revascularization.Genetics has provided additional supporting evidence for sustained elevation in arterial blood pressure causing deep intracerebral hemorrhage (ICH). In 2011, the burden of risk alleles for elevated blood pressure had been shown to associate with stroke, among other cardiovascular outcomes.6 However, this study did not specifically assess the phenotypes of lobar and deep ICH. This year, a meta-analysis reported that blood pressure–based unweighted genetic risk score was associated with risk of deep, but not lobar, ICH.7 The genetic risk score involved 38 SNPs that were not in high linkage disequilibrium. Interestingly, the association with deep ICH was predominantly observed in patients not diagnosed with hypertension before stroke, suggesting misclassification.Skeptics of genetics often question the value to public health of finding weak associations between gene variants and disease. A balanced assessment would suggest that the therapeutic gains have thus far been modest.8 However, genetics can be leveraged to guide drug development. A recent example that is relevant to stroke prevention is a Mendelian randomization study of the interleukin (IL)-6 receptor gene.9 In this study, investigators were able to demonstrate that a surrogate SNP in high linkage disequilibrium with a nonsynonymous SNP in the IL6R gene was associated with increased circulating IL-6. They also showed that the same SNP was associated with reduced risk of coronary artery disease events. Because circulating IL-6 rises with pharmacological blockade of the IL-6 receptor with the rheumatoid arthritis drug tocilizumab, the study suggests that the drug might reduce coronary artery disease events. Clearly, this theory would need to be tested with properly controlled randomized. Had IL6R SNP associated with rising circulating IL-6 been associated with increased coronary artery disease events, enthusiasm to test the drug for a new antiatherosclerosis indication would have been dampened.Mutations in the type 4 collagen A1 gene (COL4A1) can cause a small-vessel disease of the brain, which manifests with porencephaly, ICH, nephropathy, aneurysms, cramps, and diffuse white matter disease. In some of these patients, white matter hypersignal can be minimal and sometimes undetectable.10 Most mutations reported to date have been missense mutations in a conserved triple helix domain of the protein, thought to cause disease through a dominant-negative mechanism. However, 2 families with mutations leading to premature termination of message provide evidence that haploinsufficiency can cause disease.11 A case-control sequencing study of patients with sporadic ICH found rare nonsynonymous mutations in 2 of 96 patients.12 This suggests that the protein and its variation have broad importance to the pathophysiology of ICH. Mutations of the COL4A2 have now been reported to cause not only familial porencephaly but also small-vessel disease and hemorrhagic stroke in human patients.13–15 Novel molecular genetics tools also recently led to the identification of several genes involved in other stroke conditions, such as moyamoya disease and monogenic moyamoya syndromes, opening avenues to understanding the mysteries of their pathophysiology.16,17Finally, it is helpful to inform patients that conventional modifiable risk factors remain relevant, despite an unfavorable genetic background. The prospective, community-based Japan Collaborative Cohort Study, which involved >110 000 individuals, found that a parental history of stroke imparted a population-attributable fraction of risk of stroke death of 5.4% in men and 4.3% in women.18 Although significant, these numbers pale in comparison with the population-attributable fraction for stroke mortality of 45.0% in men and 43.4% in women for unhealthy lifestyle behaviors.19 Most importantly, the inverse relationship between healthy lifestyle behaviors and stroke mortality was the same, regardless of parental history of stroke. So, extinguish that cigarette, get off of the couch, and exercise; there is no sense in blaming your parents.Sources of FundingDr Meschia receives funding from the Stroke Genetics Network (SiGN) study, which is supported by the National Institute of Neurological Disorders and Stroke.DisclosuresNone.FootnotesCorrespondence to James F. Meschia, MD, Chair, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. E-mail [email protected]References1. Bevan S, Traylor M, Adib-Samii P, Malik R, Paul NL, Jackson C, et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations.Stroke. 2012; 43:3161–3167.LinkGoogle Scholar2. International Stroke Genetics Consortium Consortium (ISGS); Wellcome Trust Case Control Consortium 2 (WTCCC2); Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, et al . Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012; 44:328–333CrossrefMedlineGoogle Scholar3. Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, et al; Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2); International Stroke Genetics Consortium. 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Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency.Hum Mol Genet. 2013; 22:391–397.CrossrefMedlineGoogle Scholar12. Weng YC, Sonni A, Labelle-Dumais C, de Leau M, Kauffman WB, Jeanne M, et al. COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.Ann Neurol. 2012; 71:470–477.CrossrefMedlineGoogle Scholar13. Verbeek E, Meuwissen ME, Verheijen FW, Govaert PP, Licht DJ, Kuo DS, et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease.Eur J Hum Genet. 2012; 20:844–851.CrossrefMedlineGoogle Scholar14. Yoneda Y, Haginoya K, Arai H, Yamaoka S, Tsurusaki Y, Doi H, et al. De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly.Am J Hum Genet. 2012; 90:86–90.CrossrefMedlineGoogle Scholar15. Jeanne M, Labelle-Dumais C, Jorgensen J, Kauffman WB, Mancini GM, Favor J, et al. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.Am J Hum Genet. 2012; 90:91–101.CrossrefMedlineGoogle Scholar16. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.PLoS ONE. 2011; 6:e22542.CrossrefMedlineGoogle Scholar17. Miskinyte S, Butler MG, Hervé D, Sarret C, Nicolino M, Petralia JD, et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya.Am J Hum Genet. 2011; 88:718–728.CrossrefMedlineGoogle Scholar18. Eguchi E, Iso H, Wada Y, Kikuchi S, Watanabe Y, Tamakoshi A; Japan Collaborative Cohort Study Group. Parental history and lifestyle behaviors in relation to mortality from stroke among Japanese men and women: the Japan Collaborative Cohort Study.J Epidemiol. 2012; 22:331–339.CrossrefMedlineGoogle Scholar19. Eguchi E, Iso H, Tanabe N, Wada Y, Yatsuya H, Kikuchi S, et al; Japan Collaborative Cohort Study Group. Healthy lifestyle behaviours and cardiovascular mortality among Japanese men and women: the Japan collaborative cohort study.Eur Heart J. 2012; 33:467–477.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByBernhardt J, Zorowitz R, Becker K, Keller E, Saposnik G, Strbian D, Dichgans M, Woo D, Reeves M, Thrift A, Kidwell C, Olivot J, Goyal M, Pierot L, Bennett D, Howard G, Ford G, Goldstein L, Planas A, Yenari M, Greenberg S, Pantoni L, Amin-Hanjani S and Tymianski M (2018) Advances in Stroke 2017, Stroke, 49:5, (e174-e199), Online publication date: 1-May-2018. Calling S, Li X, Kawakami N, Hamano T and Sundquist K (2016) Impact of neighborhood resources on cardiovascular disease: a nationwide six-year follow-up, BMC Public Health, 10.1186/s12889-016-3293-5, 16:1, Online publication date: 1-Dec-2016. Mehndiratta P, Chapman Smith S and Worrall B (2014) Etiologic Stroke Subtypes: Updated Definition and Efficient Workup Strategies, Current Treatment Options in Cardiovascular Medicine, 10.1007/s11936-014-0357-7, 17:1, Online publication date: 1-Jan-2015. Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H, Mukasa A, Nakatomi H, Shimizu T and Saito N (2013) Genetic Variant RNF213 c.14576G>A in Various Phenotypes of Intracranial Major Artery Stenosis/Occlusion, Stroke, 44:10, (2894-2897), Online publication date: 1-Oct-2013. Calling S, Ji J, Sundquist J, Sundquist K and Zöller B (2013) Shared and non-shared familial susceptibility of coronary heart disease, ischemic stroke, peripheral artery disease and aortic disease, International Journal of Cardiology, 10.1016/j.ijcard.2013.03.149, 168:3, (2844-2850), Online publication date: 1-Oct-2013. February 2013Vol 44, Issue 2 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.111.000480PMID: 23321446 Manuscript receivedDecember 12, 2012Manuscript acceptedDecember 19, 2012Originally publishedJanuary 15, 2013 KeywordsreviewgenomicsstrokegeneticsPDF download Advertisement