Current Neurology and Neuroscience Reports

, Volume 9, Issue 1, pp 19–27

Genetics of ischemic stroke: Inheritance of a sporadic disorder

Article

Abstract

Stroke is a common neurologic disorder associated with comorbidities such as obesity, hypertension, hypercholesterolemia, and diabetes mellitus. Smoking or being the first-degree relative of a stroke patient can independently almost double the risk of ischemic stroke, supporting the hypothesis that stroke results from an intricate interplay between genes and the environment. Several candidate genes have been nominated but not confirmed as influencing stroke susceptibility and phenotype. A number of genes involved in monogenic forms of disease have been identified as causative in familial stroke. Herein we discuss these genes and the potential role of genetics in the more common sporadic form of stroke and therapeutic intervention strategies.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Redon R, Ishikawa S, Fitch KR, et al.: Global variation in copy number in the human genome. Nature 2006, 444:444–454.PubMedCrossRefGoogle Scholar
  2. 2.
    Wong KK, Deleeuw RJ, Dosanjh NS, et al.: A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 2007, 80:91–104.PubMedCrossRefGoogle Scholar
  3. 3.
    Mackay J, Mensah G: The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004.Google Scholar
  4. 4.
    Williams GR: Incidence and characteristics of total stroke in the United States. BMC Neurol 2001, 1:2.PubMedCrossRefGoogle Scholar
  5. 5.
    Kleindorfer D, Panagos P, Pancioli A, et al.: Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke 2005, 36:720–723.PubMedCrossRefGoogle Scholar
  6. 6.
    Leary MC, Saver JL: Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis 2003, 16:280–285.PubMedCrossRefGoogle Scholar
  7. 7.
    Flossmann E, Schulz UG, Rothwell PM: Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 2004, 35:212–227.PubMedCrossRefGoogle Scholar
  8. 8.
    Winkelmann BR, Russ AP, Nauck M, et al.: Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease. Am Heart J 1999, 137(4 Pt 1):698–705.PubMedCrossRefGoogle Scholar
  9. 9.
    Cambien F, Poirier O, Lecerf L, et al.: Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992, 359:641–644.PubMedCrossRefGoogle Scholar
  10. 10.
    Lehmann DJ, Cortina-Borja M, Warden DR, et al.: Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol 2005, 162:305–317.PubMedCrossRefGoogle Scholar
  11. 11.
    Sharma P: Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998, 64:227–230.PubMedCrossRefGoogle Scholar
  12. 12.
    Rigat B, Hubert C, Alhenc-Gelas F, et al.: An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990, 86:1343–1346.PubMedCrossRefGoogle Scholar
  13. 13.
    Bersano A, Ballabio E, Bresolin N, Candelise L: Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 2008, 29:776–795.PubMedCrossRefGoogle Scholar
  14. 14.
    Syvanen AC: Toward genome-wide SNP genotyping. Nat Genet 2005, 37(Suppl):S5–S10.PubMedCrossRefGoogle Scholar
  15. 15.
    Matarin M, Brown WM, Scholz S, et al.: A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release. Lancet Neurol 2007, 6:414–420.PubMedCrossRefGoogle Scholar
  16. 16.
    Farrer MJ, Haugarvoll K, Ross OA, et al.: Genomewide association, Parkinson disease, and PARK10. Am J Hum Genet 2006, 78:1084–1088; author reply 1092–1094.PubMedCrossRefGoogle Scholar
  17. 17.
    Helgadottir A, Thorleifsson G, Manolescu A, et al.: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007, 316:1491–1493.PubMedCrossRefGoogle Scholar
  18. 18.
    McPherson R, Pertsemlidis A, Kavaslar N, et al.: A common allele on chromosome 9 associated with coronary heart disease. Science 2007, 316:1488–1491.PubMedCrossRefGoogle Scholar
  19. 19.
    Abdullah KG, Li L, Shen GQ, et al.: Four SNPS on chromosome 9p21 confer risk to premature, familial CAD and MI in an American Caucasian population (GeneQuest). Ann Hum Genet 2008, 72(Pt 5):654–657.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen Z, Qian Q, Ma G, et al.: A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease. Mol Biol Rep 2008 May 6 (Epub ahead of print).Google Scholar
  21. 21.
    Helgadottir A, Thorleifsson G, Magnusson KP, et al.: The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008, 40:217–224.PubMedCrossRefGoogle Scholar
  22. 22.
    Hiura Y, Fukushima Y, Yuno M, et al.: Validation of the association of genetic variants on chromosome 9p21 and 1q41 with myocardial infarction in a Japanese population. Circ J 2008, 72:1213–1217.PubMedCrossRefGoogle Scholar
  23. 23.
    Matarin M, Brown WM, Singleton A, et al.: Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21. Stroke 2008, 39:1586–1589.PubMedCrossRefGoogle Scholar
  24. 24.
    Gretarsdottir S, Thorleifsson G, Reynisdottir ST, et al.: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003, 35:131–138.PubMedCrossRefGoogle Scholar
  25. 25.
    Zee RY, Brophy VH, Cheng S, et al.: Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke 2006, 37:2012–2017.PubMedCrossRefGoogle Scholar
  26. 26.
    Bevan S, Porteous L, Sitzer M, Markus HS: Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke 2005, 36:949–953.PubMedCrossRefGoogle Scholar
  27. 27.
    Meschia JF, Brott TG, Brown RD Jr, et al.: Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol 2005, 58:351–361.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosand J, Bayley N, Rost N, de Bakker PI: Many hypotheses but no replication for the association between PDE4D and stroke. Nat Genet 2006, 38:1091–1092; author reply 1092–1093.PubMedCrossRefGoogle Scholar
  29. 29.
    Bevan S, Dichgans M, Gschwendtner A, et al.: Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls. Stroke 2008, 39:1966–1971.PubMedCrossRefGoogle Scholar
  30. 30.
    Helgadottir A, Manolescu A, Thorleifsson G, et al.: The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004, 36:233–239.PubMedCrossRefGoogle Scholar
  31. 31.
    Helgadottir A, Gretarsdottir S, St Clair D, et al.: Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 2005, 76:505–509.PubMedCrossRefGoogle Scholar
  32. 32.
    Bevan S, Dichgans M, Wiechmann HE, et al.: Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke: a replication study in two independent populations. Stroke 2008, 39:1109–1114.PubMedCrossRefGoogle Scholar
  33. 33.
    Ducros A, Nagy T, Alamowitch S, et al.: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval. Am J Hum Genet 1996, 58:171–181.PubMedGoogle Scholar
  34. 34.
    Tournier-Lasserve E, Joutel A, Melki J, et al.: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993, 3:256–259.PubMedCrossRefGoogle Scholar
  35. 35.
    Joutel A, Corpechot C, Ducros A, et al.: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996, 383:707–710.PubMedCrossRefGoogle Scholar
  36. 36.
    Fouillade C, Chabriat H, Riant F, et al.: Activating NOTCH3 mutation in a patient with small-vessel-disease of the brain. Hum Mutat 2008, 29:452.PubMedCrossRefGoogle Scholar
  37. 37.
    Pescini F, Bianchi S, Salvadori E, et al.: A pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. J Neurol Sci 2008, 267:170–173.PubMedCrossRefGoogle Scholar
  38. 38.
    Pradotto L, Azan G, Doriguzzi C, et al.: Sporadic vascular dementia as clinical presentation of a new missense mutation within exon 7 of NOTCH3 gene. J Neurol Sci 2008, 271:207–210.PubMedCrossRefGoogle Scholar
  39. 39.
    Guttmacher AE, Collins FS: Welcome to the genomic era. N Engl J Med 2003, 349:996–998.PubMedCrossRefGoogle Scholar
  40. 40.
    Collins FS, Green ED, Guttmacher AE, Guyer MS: A vision for the future of genomics research. Nature 2003, 422:835–847.PubMedCrossRefGoogle Scholar
  41. 41.
    Cortese DA: A vision of individualized medicine in the context of global health. Clin Pharmacol Ther 2007, 82:491–493.PubMedCrossRefGoogle Scholar
  42. 42.
    Adams RJ, Albers G, Alberts MJ, et al.: Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008, 39:1647–1652.PubMedCrossRefGoogle Scholar
  43. 43.
    Goldstein LB, Adams R, Alberts MJ, et al.: Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2006, 113:e873–e923.PubMedCrossRefGoogle Scholar
  44. 44.
    Jacobson TA: “The lower the better” in hypercholesterolemia therapy: a reliable clinical guideline? Ann Intern Med 2000, 133:549–554.PubMedGoogle Scholar
  45. 45.
    Halliday A, Mansfield A, Marro J, et al.: Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004, 363:1491–1502.PubMedCrossRefGoogle Scholar
  46. 46.
    Henriksson M, Lundgren F, Carlsson P: Cost-effectiveness of endarterectomy in patients with asymptomatic carotid artery stenosis. Br J Surg 2008, 95:714–720.PubMedCrossRefGoogle Scholar
  47. 47.
    Mohr JP, Thompson JL, Lazar RM, et al.: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001, 345:1444–1451.PubMedCrossRefGoogle Scholar
  48. 48.
    Homma S, Sacco RL, Di Tullio MR, et al.: Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002, 105:2625–2631.PubMedCrossRefGoogle Scholar
  49. 49.
    Levine SR, Brey RL, Tilley BC, et al.: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 2004, 291:576–584.PubMedCrossRefGoogle Scholar
  50. 50.
    Gretarsdottir S, Gudmar T, Manolescu A, et al.: Risk variants for atrial fibrillation on 4q25 associate with ischemic stroke. Ann Neurol (in press).Google Scholar
  51. 51.
    Meschia JF: Decoding cryptogenic cardioembolism. Ann Neurol 2008, 64:364–366.PubMedCrossRefGoogle Scholar
  52. 52.
    Messe SR, Silverman IE, Kizer JR, et al.: Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004, 62:1042–1050.PubMedGoogle Scholar
  53. 53.
    Farrer MJ: Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006, 7:306–318.PubMedCrossRefGoogle Scholar
  54. 54.
    Singleton AB, Farrer M, Johnson J, et al.: alpha-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302:841.PubMedCrossRefGoogle Scholar
  55. 55.
    Maraganore DM, de Andrade M, Elbaz A, et al.: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006, 296:661–670.PubMedCrossRefGoogle Scholar
  56. 56.
    Di Fonzo A, Wu-Chou YH, Lu CS, et al.: A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 2006, 7:133–138.PubMedCrossRefGoogle Scholar
  57. 57.
    Ross OA, Wu YR, Lee MC, et al.: Analysis of Lrrk2 R1628P as a risk factor for Parkinson’s disease. Ann Neurol 2008, 64:88–92.PubMedCrossRefGoogle Scholar
  58. 58.
    Arboleda-Velasquez JF, Zhou Z, Shin HK, et al.: Linking Notch signaling to ischemic stroke. Proc Natl Acad Sci U S A 2008, 105:4856–4861.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2009

Authors and Affiliations

  1. 1.Department of NeurologyMayo Clinic FloridaJacksonvilleUSA

Personalised recommendations