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Advances in Stroke 2009

2010; Lippincott Williams & Wilkins; Volume: 41; Issue: 2 Linguagem: Esloveno

10.1161/strokeaha.109.571034

1524-4628

Robert A. Hegele, Martin Dichgans,

Neurological Disorders and Treatments

HomeStrokeVol. 41, No. 2Advances in Stroke 2009 Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBAdvances in Stroke 2009Update on the Genetics of Stroke and Cerebrovascular Disease 2009 Robert A. Hegele, MD, FRCPC and Martin Dichgans, MD Robert A. HegeleRobert A. Hegele From the Robarts Research Institute and Schulich School of Medicine and Dentistry (R.A.H.), University of Western Ontario, London, Canada, and the Neurologische Klinik and Institute for Stroke and Dementia Research, Klinikum Großhadern (M.D.), Ludwig-Maximilians-Universität, Munich, Germany. and Martin DichgansMartin Dichgans From the Robarts Research Institute and Schulich School of Medicine and Dentistry (R.A.H.), University of Western Ontario, London, Canada, and the Neurologische Klinik and Institute for Stroke and Dementia Research, Klinikum Großhadern (M.D.), Ludwig-Maximilians-Universität, Munich, Germany. Originally published14 Jan 2010https://doi.org/10.1161/STROKEAHA.109.571034Stroke. 2010;41:e63–e66Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 14, 2010: Previous Version 1 2009 will be remembered as the year that genome-wide association studies (GWAS) revealed both their promise and limitations as an approach to understand the genetic architecture of stroke. The promise of GWAS lies in their extraordinary power to detect novel biologic loci that, if replicated, can serve as markers for novel genes, proteins, and ultimately mechanisms of disease. In this regard, since our previously yearly review,1 new GWAS from 2009 suggested that loci on chromosomes 4q25 (PITX2 gene, encoding a β-catenin–regulated transcription factor associated with atrial fibrillation),2 16q22 (ZFHX3 gene, encoding a homeodomain zinc-finger protein that has also been associated with atrial fibrillation),3 and 12p13 (NINJ2 gene, encoding a protein that is upregulated by nerve injury)4 could be added to the list of stroke-associated loci identified from earlier studies. The mechanistic basis for the associations with genetic markers across the spectrum of stroke-associated loci can now be explored.However, the limitations of stroke GWAS have also become apparent. These include the fact that so far, no locus has been replicated in 2 independent study samples. Indeed, targeted experiments in independent samples that have studied positive hits from earlier stroke GWAS have generally not replicated the initial positive findings.5 This could indicate that the "ischemic stroke" phenotype is very heterogeneous between study sample populations and as such needs to be narrowed or made more specific. Perhaps future experiments might more fruitfully evaluate specific subphenotypes or account for genetic determinants of risk factors for stroke, such as lipids6,7 or blood pressure.8,9 Stroke GWAS can also be performed with presymptomatic phenotypes. For instance, several new loci were associated with carotid intima-media thickness (IMT) as measured by ultrasound.10 It might also be informative to evaluate the genetic basis of stroke and its related phenotypes in different ethnic groups.Importantly, the effect sizes identified in the positive GWAS of stroke were modest, a general feature of GWAS that has raised concerns that the results may not have clinical relevance.11 Finding other loci will require even larger sample sizes to detect even smaller effect sizes, and these in turn might be even less likely to have clinical relevance. However, there is general consensus that at least some of the loci identified in GWAS will be shown to have revealed a new aspect of previously unappreciated stroke biology.12 GWAS of stroke and related traits will thus continue to populate the literature for the foreseeable future.Rare Mutations and Stroke-Related PhenotypesAlthough attention has recently been focused on common variants in GWAS that predispose to stroke and related phenotypes in the general population, the mapping of genes with mutations that cause rare mendelian forms of stroke-related phenotypes continues apace. For instance, the vascular smooth muscle cell (SMC)–specific isoform of α-actin (ACTA2) is expressed throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAADs) in most but not all mutation carriers. Recently, gene mapping studies in affected individuals in 20 families with ACTA2 mutations showed that mutation carriers expressed a wider range of vascular diseases than previously expected, including premature coronary artery disease, premature ischemic strokes, premature Moyamoya disease (MMD), as well as TAADs. Sequencing of the genomic DNA from patients with nonfamilial TAADs also identified ACTA2 mutations,13 with premature strokes in some mutation carriers. These findings add to the notion that sequence variants in a single gene or genomic region may be associated with multiple arterial phenotypes, as previously shown for the chromosome 9p21 region.1 Vascular pathology and cell biology studies indicated that the mutant ACTA2 was associated with increased SMC proliferation and vaso-occlusion. This gene now becomes one that needs to be considered in future studies of familial cerebrovascular disease.13Another example of a single-gene form of familial cerebrovascular ischemia is cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an extraordinarily rare phenotype characterized by ischemic, nonhypertensive, cerebral small-vessel disease associated with alopecia and spondylosis.14 In 5 families with CARASIL, the disease was linked to a 2.4-Mbase region on chromosome 10q that contains the HTRA1 gene encoding serine protease 1, which normally represses cell signaling by transforming growth factor-β. Sequencing of DNA from study subjects revealed 2 nonsense mutations and 2 missense mutations in HTRA1, each of which showed functional impairment in vitro.14 The findings indicate a link between repressed inhibition of signaling by the transforming growth factor-β family and ischemic cerebral small-vessel disease and thus represent another new gene to be considered in future studies of familial cerebrovascular disease.Genetics of Cerebral Cavernous MalformationsFurther progress has been made on cerebral cavernous malformations (CCMs). Familial cases usually display multiple lesions, follow an autosomal dominant inheritance, and are caused by mutations in 1 of at least 3 genes, CCM1/KRIT1, CCM2/malcavernin, or CCM3/PDCD10. It has been speculated that CCM lesions originate from a 2-hit molecular mechanism, which requires the second allele not affected by the germline mutation to be hit by a somatic mutation. This mechanism, which results in the inactivation of both alleles, has recently been confirmed for all 3 forms of inherited CCMs. Through repeated cycles of amplification, subcloning, and sequencing, Akers et al15 identified somatic mutations in a subset of endothelial cells lining the cavernous vessels. Complementing these findings, other investigators demonstrated a lack of expression of CCM proteins specifically within endothelial cells.16 These observations define cavernous endothelial cells as the primary disease compartment while suggesting a key role for CCM proteins in endothelial cell biology.Gene Expression ProfilingAnother expanding area has been the analysis of gene expression profiles in tissues and circulating cells by using microarrays.17 Arrays for various species and applications are currently on the market. These arrays can analyze the mRNA expression levels of tens of thousands of genes in tissue preparations from patients or experimental animals and compare them with controls. Investigators are then often left with hundreds of differentially expressed genes, each of which needs to be validated and interpreted in a meaningful way. For instance, a recent study on white-matter lesions identified 509 genes that were differentially expressed compared with normal white matter from healthy controls.18 These genes could be broadly grouped into 8 major pathways, including immune regulation, cell cycle, apoptosis, and ion transport. Another study on intracranial aneurysms found 326 genes that were differentially expressed compared with those in healthy arteries from the same patients. Bioinformatics pathway analysis revealed that many of these genes could be attributed to 1 of the following pathways: focal adhesion, extracellular matrix receptor interaction, and cell communication.19 Yet, despite such progress, the critical players still need to be identified.Furthermore, the biology behind these altered expression profiles requires disentanglement. In this regard, studies in experimental stroke models have demonstrated particular progress. For instance, microarray analysis of brains collected 24 hours after experimental stroke have revealed new mechanisms of neuroprotection mediated by lipopolysaccharide preconditioning.20 Another example is the discovery of altered gene expression profiles associated with inosine-induced axonal outgrowth and functional recovery after cortical stroke. Inosine was shown to attenuate transcriptional changes caused by stroke while upregulating the expression of genes associated with axon growth. Although promising, gene expression profiling is still in its infancy, and various technical issues complicate the reproducibility of microarray-related data.21PharmacogenomicsThe promise of individualized therapy to prevent stroke incidence or recurrence based on a more rational approach to the selection of an agent and dose based on an individual's genetic profile came incrementally closer to clinical reality in 2009. The antiplatelet agents clopidogrel and prasugrel in particular received considerable attention. For instance, individual response to clopidogrel was found to vary, based on genetic differences in the CYP genes encoding the drug-metabolizing cytochrome P450 enzymes. Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had lower blood levels of the drug's active metabolite, less platelet inhibition, and increased major adverse cardiovascular events than did noncarriers.22 In contrast, similar relationships were not observed with genetic markers of the same enzymes for individuals treated with prasugrel.23 This could in part explain the observed differences in the pharmacologic and clinical responses to the 2 medications.However, in a broader sense, the clinical relevance of such findings remains uncertain. For instance, >2 years after the United States Food and Drug Administration approved the principle of genotyping of patients on warfarin of CYP2C9 and VKORC1, 2 genes that are involved in the response to warfarin,24 such testing is not yet routine in the clinic. This is because the cost-benefit and clinical utility of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin are still uncertain. Interestingly, a recent report showed that an algorithm that incorporates CYP2C9 and VKORC1 genotyping allows patients who require extreme warfarin doses to more efficiently reach their stable therapeutic dose than does a purely empirical regimen.25 However, there appears to be no benefit of this algorithm for individuals in the middle of the distribution of warfarin dose requirement. As is almost always the case with genetic association studies, replication of these early observations is required.OutlookThe genetics of stroke remains a rapidly developing field. The coming months and years will see additional GWAS on ischemic stroke, hemorrhagic stroke, and related phenotypes, such as white-matter hyperintensities and intima-media thickness. Rare variants in families with rare mendelian forms of stroke will continue to provide information about new genes associated with the overall genetic risk of stroke. Expectations remain high that genetic discoveries will eventually be translated into improved diagnostics and treatment.Sources of FundingR.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Genetics, a Career Investigator award from the Heart and Stroke Foundation of Ontario, operating grants from the Canadian Institutes for Health Research (MOP-13430, MT-8014), the Heart and Stroke Foundation of Ontario (NA-5320, T-5603, PRG-5967), and Genome Canada through the Ontario Genomics Institute. M.D. is supported by grants from the Wellcome Trust and by the Vascular Dementia Research Foundation.DisclosuresNone.FootnotesCorrespondence to Robert A. Hegele, MD, FRCPC, FACP, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada. E-mail [email protected] References 1 Dichgans M, Hegele RA. Update on the genetics of stroke and cerebrovascular disease 2008. Stroke. 2009; 40: e289–e291.LinkGoogle Scholar2 Gretarsdottir S, Thorleifsson G, Manolescu A, Styrkarsdottir U, Helgadottir A, Gschwendtner A, Kostulas K, Kuhlenbaumer G, Bevan S, Jonsdottir T, Bjarnason H, Saemundsdottir J, Palsson S, Arnar DO, Holm H, Thorgeirsson G, Valdimarsson EM, Sveinbjornsdottir S, Gieger C, Berger K, Wichmann HE, Hillert J, Markus H, Gulcher JR, Ringelstein EB, Kong A, Dichgans M, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol. 2008; 64: 402–409.CrossrefMedlineGoogle Scholar3 Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, Gulcher J, Mathiesen EB, Njolstad I, Nyrnes A, Wilsgaard T, Hald EM, Hveem K, Stoltenberg C, Kucera G, Stubblefield T, Carter S, Roden D, Ng MC, Baum L, So WY, Wong KS, Chan JC, Gieger C, Wichmann HE, Gschwendtner A, Dichgans M, Kuhlenbaumer G, Berger K, Ringelstein EB, Bevan S, Markus HS, Kostulas K, Hillert J, Sveinbjornsdottir S, Valdimarsson EM, Lochen ML, Ma RC, Darbar D, Kong A, Arnar DO, Thorsteinsdottir U, Stefansson K. A sequence variant in zfhx3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009; 41: 876–878.CrossrefMedlineGoogle Scholar4 Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS, Debette S, Lumley T, Folsom AR, van den Herik EG, Bos MJ, Beiser A, Cushman M, Launer LJ, Shahar E, Struchalin M, Du Y, Glazer NL, Rosamond WD, Rivadeneira F, Kelly-Hayes M, Lopez OL, Coresh J, Hofman A, DeCarli C, Heckbert SR, Koudstaal PJ, Yang Q, Smith NL, Kase CS, Rice K, Haritunians T, Roks G, de Kort PL, Taylor KD, de Lau LM, Oostra BA, Uitterlinden AG, Rotter JI, Boerwinkle E, Psaty BM, Mosley TH, van Duijn CM, Breteler MM, Longstreth WT Jr, Wolf PA. Genomewide association studies of stroke. N Engl J Med. 2009; 360: 1718–1728.CrossrefMedlineGoogle Scholar5 Matarin M, Brown WM, Dena H, Britton A, De Vrieze FW, Brott TG, Brown RD Jr, Worrall BB, Case LD, Chanock SJ, Metter EJ, Ferruci L, Gamble D, Hardy JA, Rich SS, Singleton A, Meschia JF. Candidate gene polymorphisms for ischemic stroke. Stroke. 2009; 40: 3436–3442.LinkGoogle Scholar6 Hegele RA. Plasma lipoproteins: genetic influences and clinical implications. Nat Rev Genet. 2009; 10: 109–121.CrossrefMedlineGoogle Scholar7 Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009; 41: 56–65.CrossrefMedlineGoogle Scholar8 Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009 May 10 [Epub ahead of print].Google Scholar9 Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J, Burton PR, Hadley D, McArdle WL, Brown M, Dominiczak A, Newhouse SJ, Samani NJ, Webster J, Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K, Vollenweider P, Waeber G, Waterworth DM, Yuan X, Groop L, Orho-Melander M, Allione A, Di Gregorio A, Guarrera S, Panico S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, Sandhu MS, Luben RN, Crawford GJ, Jousilahti P, Perola M, Boehnke M, Bonnycastle LL, Collins FS, Jackson AU, Mohlke KL, Stringham HM, Valle TT, Willer CJ, Bergman RN, Morken MA, Doring A, Gieger C, Illig T, Meitinger T, Org E, Pfeufer A, Wichmann HE, Kathiresan S, Marrugat J, O'Donnell CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer NB, Hartikainen AL, McCarthy MI, O'Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf U, Syvanen AC, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Dorr M, Ernst F, Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig R, Volker U, Galan P, Gut IG, Hercberg S, Lathrop GM, Zelenika D, Deloukas P, Soranzo N, Williams FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi NG, Volzke H, Uiterwaal CS, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bingham SA, Kooner JS, Connell JM, Bandinelli S, Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Altshuler D, Strachan DP, Laan M, Meneton P, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009; 41: 666–676.CrossrefMedlineGoogle Scholar10 Lanktree MB, Hegele RA, Yusuf S, Anand SS. Multi-ethnic genetic association study of carotid intima-media thickness using a targeted cardiovascular snp microarray. Stroke. 2009; 40: 3173–3179.LinkGoogle Scholar11 Goldstein DB. Common genetic variation and human traits. N Engl J Med. 2009; 360: 1696–1698.CrossrefMedlineGoogle Scholar12 Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009; 360: 1759–1768.CrossrefMedlineGoogle Scholar13 Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM. Mutations in smooth muscle α-actin (ACTA2) cause coronary artery disease, stroke, and moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009; 84: 617–627.CrossrefMedlineGoogle Scholar14 Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura M, Shimoe Y, Hirayama M, Arisato T, Yanagawa S, Tanaka A, Nakano I, Ikeda S, Yoshida Y, Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M, Tsuji S, Onodera O. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009; 360: 1729–1739.CrossrefMedlineGoogle Scholar15 Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet. 2009; 18: 919–930.CrossrefMedlineGoogle Scholar16 Pagenstecher A, Stahl S, Sure U, Felbor U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum Mol Genet. 2009; 18: 911–918.CrossrefMedlineGoogle Scholar17 Nygaard V, Hovig E. Methods for quantitation of gene expression. Front Biosci. 2009; 14: 552–569.Google Scholar18 Simpson JE, Hosny O, Wharton SB, Heath PR, Holden H, Fernando MS, Matthews F, Forster G, O'Brien JT, Barber R, Kalaria RN, Brayne C, Shaw PJ, Lewis CE, Ince PG. Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways. Stroke. 2009; 40: 369–375.LinkGoogle Scholar19 Shi C, Awad IA, Jafari N, Lin S, Du P, Hage ZA, Shenkar R, Getch CC, Bredel M, Batjer HH, Bendok BR. Genomics of human intracranial aneurysm wall. Stroke. 2009; 40: 1252–1261.LinkGoogle Scholar20 Marsh B, Stevens SL, Packard AE, Gopalan B, Hunter B, Leung PY, Harrington CA, Stenzel-Poore MP. Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci. 2009; 29: 9839–9849.CrossrefMedlineGoogle Scholar21 Ioannidis JP, Allison DB, Ball CA, Coulibaly I, Cui X, Culhane AC, Falchi M, Furlanello C, Game L, Jurman G, Mangion J, Mehta T, Nitzberg M, Page GP, Petretto E, van Noort V. Repeatability of published microarray gene expression analyses. Nat Genet. 2009; 41: 149–155.CrossrefMedlineGoogle Scholar22 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360: 354–362.CrossrefMedlineGoogle Scholar23 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome p450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009; 119: 2553–2560.LinkGoogle Scholar24 Woodcock J, Woosley R. The FDA critical path initiative and its influence on new drug development. Annu Rev Med. 2008; 59: 1–12.CrossrefMedlineGoogle Scholar25 Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009; 360: 753–764.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Guo X, Zhu L, Zhao X, Wu X, Yang J, Huang J, Gu L and Su L (2021) Influence of the rs6736 Polymorphism on Ischemic Stroke Susceptibility in Han Chinese Individuals via the Disruption of miR-7–1 Binding to the C14orf119 Gene, Journal of Molecular Neuroscience, 10.1007/s12031-021-01895-7, 72:3, (459-467), Online publication date: 1-Mar-2022. Adwan-Shekhidem H and Atzmon G (2018) The Epigenetic Regulation of Telomere Maintenance in Aging Epigenetics of Aging and Longevity, 10.1016/B978-0-12-811060-7.00005-X, (119-136), . ZAKAI N, LANGE L, LONGSTRETH W, O'MEARA E, KELLEY J, FORNAGE M, NIKERSON D, CUSHMAN M and REINER A (2011) Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2010.04149.x, 9:2, (267-274), Online publication date: 1-Feb-2011. Wang C, Sun T, Li H, Bai J and Li Y (2011) Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: A meta-analysis, Thrombosis Research, 10.1016/j.thromres.2011.07.016, 128:5, (e107-e112), Online publication date: 1-Nov-2011. Moskowitz M, Lo E and Iadecola C (2010) The Science of Stroke: Mechanisms in Search of Treatments, Neuron, 10.1016/j.neuron.2010.07.002, 67:2, (181-198), Online publication date: 1-Jul-2010. Sellami M, Bragazzi N, Prince M, Denham J and Elrayess M (2021) Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime, Frontiers in Genetics, 10.3389/fgene.2021.652497, 12 February 2010Vol 41, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.109.571034PMID: 20075351 Manuscript receivedOctober 21, 2009Manuscript acceptedNovember 4, 2009Originally publishedJanuary 14, 2010 Keywordsstrokegeneticsgenomewide association studiesmutationspharmacogeneticsmicroarraysPDF download Advertisement