Skip to main content
SpringerLink
Log in

Cerebral Small Vessel Disease

Genetic Risk Assessment for Prevention and Treatment

  • CNS Disorders
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Cerebrovascular disease is a major burden to individuals and their communities worldwide. Stroke is one of the leading causes of death and disability, and the prevention and treatment of stroke can be improved with a better understanding of its causation. Cerebral small vessel disease (SVD) is a subset of cerebrovascular disease, and has an equally large impact on an individual’s quality of life. Although many risk factors are involved, we propose that genetics has a significant role in the pathogenesis of SVD through a complex interplay of environmental and multigenetic factors. Advances in molecular technology have enabled the human genome to be investigated both at a population and, more recently, an individual level. A better understanding of the molecular basis of SVD will enable the development of therapies to help in its prevention and treatment. This review assesses the molecular genetics underlying cerebral SVD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2

Similar content being viewed by others

References

  1. World Health Organization. The atlas of heart disease and stroke: part 1. Types of cardiovascular disease. Geneva: World Health Organization, 2004 [online]. Available from URL: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf [Accessed 2008 Apr 3]

    Google Scholar 

  2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006 Nov; 3(11): e442

    Article  PubMed  Google Scholar 

  3. World Health Organization. Ten statistical highlights in global public health. Geneva: World Health Organization, 2007

    Google Scholar 

  4. Australian Institute of Health and Welfare. Secondary prevention and rehabilitation after coronary events or stroke: a review of monitoring issues (AIHW Cat. No. CVD 25). Canberra: Australian Institute of Health and Welfare, 2003

    Google Scholar 

  5. The British Heart Foundation. Heartstats [online]. Available from URL: http://www.heartstats.org [Accessed 2007 Sep 5]

  6. The Stroke Association. The Stroke Association [online]. Available from URL: http://www.stroke.org.uk/information/index.html [Accessed 2007 Sep 5]

  7. National Stroke Association. Stroke facts [online]. Available from URL: http://www.stroke.org [Accessed 2007 Sep 5]

  8. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics, 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007 Feb; 115(5): e69–171

    Article  PubMed  Google Scholar 

  9. Hankey G. Preventing stroke: what is the real progress. Med J Aust 1999 Sep; 171(6): 285–6

    PubMed  CAS  Google Scholar 

  10. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001 Feb; 291(5507): 1304–51

    Article  PubMed  CAS  Google Scholar 

  11. Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. PLoS Biol 2007 Oct; 5(10): e254

    Article  PubMed  CAS  Google Scholar 

  12. Adams Jr HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischaemic stroke: definitions for use in a multicentre clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993 Jan; 24(1): 35–41

    Article  PubMed  Google Scholar 

  13. Ward NS, Brown MM. Leukoaraiosis. In: Donnan G, Norrving B, Bamford J, et al., editors. Subcortical stroke. New York: Oxford University Press, 2002: 47–66

    Google Scholar 

  14. Hauw JJ. The history of lacunes. In: Donnan G, Norrving B, Bamford J, et al., editors. Subcortical stroke. New York: Oxford University Press, 2002: 1–15

    Google Scholar 

  15. Sacco S, Marini C, Totaro R, et al. A population-based study of the incidence and prognosis of lacunar stroke. Neurology 2006 May; 66(9): 1335–8

    Article  PubMed  CAS  Google Scholar 

  16. Bamford J, Sandercock P, Jones L, et al. The natural history of lacunar infarction: the Oxfordshire Community Stroke Project. Stroke 1987 May; 18(3): 545–51

    Article  PubMed  CAS  Google Scholar 

  17. Samuelsson M, Soderfeldt B, Olsson GB. Functional outcome in patients with lacunar infarction. Stroke 1996 May; 27(5): 842–6

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt RJ, Enzinger C, Ropele S, et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet 2003 Jun; 361(9374): 2046–8

    Article  PubMed  Google Scholar 

  19. Leys D, Englund E, Del Ser T, et al. White matter changes in stroke patients. Eur Neurol 1999 Aug; 42(2): 67–75

    Article  PubMed  CAS  Google Scholar 

  20. Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology 1965 Aug; 15: 774–84

    Article  PubMed  CAS  Google Scholar 

  21. White RP, Vallance P, Markus H. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci 2000 Dec; 99(6): 555–60

    Article  PubMed  CAS  Google Scholar 

  22. Hassan A, Hunt BJ, O’Sullivan M, et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 2003 Feb; 126(2): 424–32

    Article  PubMed  Google Scholar 

  23. Hassan A, Hunt BJ, O’Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain 2004 Jan; 127(1): 212–9

    Article  PubMed  Google Scholar 

  24. Fisher CM. Lacunar infarcts: a review. Cardiovasc Dis 1991; 1(6): 311–20

    Google Scholar 

  25. Wardlaw JM. What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005 May; 76(5): 617–9

    Article  PubMed  CAS  Google Scholar 

  26. Lammie GA, Brannan F, Slattery J, et al. Nonhypertensive cerebral small-vessel disease: an autopsy study. Stroke 1997 Nov; 28(11): 2222–9

    Article  PubMed  CAS  Google Scholar 

  27. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol 1969 Mar; 12(1): 1–15

    Article  Google Scholar 

  28. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol 1979 Feb; 36(2): 65–73

    Article  PubMed  CAS  Google Scholar 

  29. Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982 Aug; 32(8): 871–6

    Article  PubMed  CAS  Google Scholar 

  30. Boiten J, Lodder J, Kessels F. Two clinically distinct lacunar infarct entities? A hypothesis. Stroke 1993 May; 24(5): 652–6

    Article  PubMed  CAS  Google Scholar 

  31. Lammie GA. Pathology of lacunar infarction. In: Donnan G, Norrving B, Bamford J, et al., editors. Subcortical stroke. New York: Oxford University Press, 2002: 37–46

    Google Scholar 

  32. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997 Mar; 28(3): 652–9

    Article  PubMed  CAS  Google Scholar 

  33. Inzitari D, Mascalchi M, Giordano GP, et al. Histopathological correlates of leukoaraiosis in patients with ischemic stroke. Eur Neurol 1989; 29Suppl. 2: 23–6

    Article  PubMed  Google Scholar 

  34. Szolnoki Z. Chemical events behind leukoaraiosis: medicinal chemistry offers new insight into a specific microcirculation in the brain (a chemical approach to a frequent cerebral phenotype). Curr Med Chem 2007 Apr; 14(9): 1027–36

    Article  PubMed  CAS  Google Scholar 

  35. Szolnoki Z. Pathomechanism of leukoaraiosis. Neuromol Med 2007 Feb; 9(1): 21–34

    Article  CAS  Google Scholar 

  36. de Reuck J. The human periventricular arterial blood supply and the anatomy of cerebral infarctions. Eur Neurol 1971; 5(6): 321–34

    Article  PubMed  Google Scholar 

  37. Wardlaw JM, Sandercock P, Dennis M, et al. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 2003 Mar; 34(3): 806–12

    Article  PubMed  CAS  Google Scholar 

  38. Starr JM, Wardlaw J, Ferguson K, et al. Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2003 Jan; 74(1): 70–6

    Article  PubMed  CAS  Google Scholar 

  39. Tomimoto H, Akiguchi I, Suenaga T, et al. Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer’s Disease patients. Stroke 1996 Nov; 27(11): 2069–74

    Article  PubMed  CAS  Google Scholar 

  40. Jerrard-Dunne P, Cloud G, Hassan A, et al. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 2003 Jun; 34(6): 1364–9

    Article  PubMed  Google Scholar 

  41. Polychronopoulos P, Gioldasis G, Ellul J, et al. Family history of stroke in stroke types and subtypes. J Neuro Sci 2002 Mar; 195(2): 117–22

    Article  CAS  Google Scholar 

  42. Turner ST, Jack CR, Fornage M, et al. Heritability of leukoaraiosis in hypertensive sibships. Hypertension 2004 Feb; 43(2): 483–7

    Article  PubMed  CAS  Google Scholar 

  43. Carmelli D, DeCarli C, Swan GE, et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 1998 Jun; 29(6): 1177–81

    Article  PubMed  CAS  Google Scholar 

  44. Atwood LD, Wolf PA, Heard-Costa NL, et al. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke 2004 Jul; 35(7): 1609–13

    Article  PubMed  Google Scholar 

  45. Szolnoki Z, Havasi V, Bene J, et al. Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke. Acta Neurol Scand 2005 Jan; 111(1): 29–33

    Article  PubMed  CAS  Google Scholar 

  46. Hassan A, Gormley K, O’Sullivan M, et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 2004 Mar; 35(3): 654–9

    Article  PubMed  CAS  Google Scholar 

  47. Gormley K, Bevan S, Hassan A, et al. Polymorphisms in genes of the endothelin system and cerebral small-vessel disease. Stroke 2005 Aug; 36(8): 1656–60

    Article  PubMed  CAS  Google Scholar 

  48. INSERM. GeneCanvas [online]. Available from URL: http://genecanvas.idf.inserm.fr [Accessed 2007 Sep 5]

  49. Markus HS, Barley J, Lunt R, et al. Angiotensin-converting enzyme gene deletion polymorphism: a new risk factor for lacunar stroke but not carotid atheroma. Stroke 1995 Aug; 26(8): 1329–33

    Article  PubMed  CAS  Google Scholar 

  50. Szolnoki Z, Somogyvari F, Kondacs A, et al. Evaluation of the interactions of common genetic mutations in stroke subtypes. J Neurol 2002 Oct; 249(10): 1391–7

    Article  PubMed  CAS  Google Scholar 

  51. Szolnoki Z, Somogyvari F, Kondacs A, et al. Evaluation of the roles of common genetic mutations in leukoaraiosis. Acta Neurol Scand 2001 Nov; 104(5): 281–7

    Article  PubMed  CAS  Google Scholar 

  52. Schmidt R, Schmidt H, Fazekas F, et al. Angiotensinogen polymorphism M235T, carotid atherosclerosis, and small-vessel disease-related cerebral abnormalities. Hypertension 2001 Jul; 38(1): 110–5

    Article  PubMed  CAS  Google Scholar 

  53. Zhang JH, Kohara K, Yamamoto Y, et al. Genetic predisposition to neurological symptoms in lacunar infarction. Cerebrovasc Dis 2004 May; 17(4): 273–9

    Article  PubMed  Google Scholar 

  54. Takami S, Imai Y, Katsuya T, et al. Gene polymorphism of the renin-angiotensin system associates with risk for lacunar infarction: the Ohasama study. Am J Hyperten 2000 Feb; 13(2): 121–7

    Article  CAS  Google Scholar 

  55. Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: the NILS-LSA study. Stroke 2003 May; 34(5): 1130–5

    Article  PubMed  Google Scholar 

  56. Li Z, Sun L, Zhang H, et al. Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a multicenter case-control study in China. Stroke 2003 Sep; 34(9): 2085–90

    Article  PubMed  CAS  Google Scholar 

  57. Martiskainen M, Pohjasvaara T, Mikkelsson J, et al. Fibrinogen gene promoter −455 A allele as a risk factor for lacunar stroke. 2003 Apr; 34(4): 886–91

    CAS  Google Scholar 

  58. Jannes J, Hamilton-Bruce M, Pilotto L, et al. Tissue plasminogen activator −7351C/T enhancer polymorphism is a risk factor for lacunar stroke. Stroke 2004 May; 35(5): 1090–4

    Article  PubMed  CAS  Google Scholar 

  59. Jood K, Ladenvall P, Tjarnlund-Wolf A, et al. Fibrinolytic gene polymorphism and ischemic stroke. Stroke 2005 Oct; 36(10): 2077–81

    Article  PubMed  CAS  Google Scholar 

  60. Armstrong CA, Bevan SN, Gormley KT, et al. Tissue plasminogen activator −7351C/T polymorphism and lacunar stroke ‘response’. Stroke 2006 Feb; 37(2): 329–30

    Article  PubMed  Google Scholar 

  61. Chamorro A, Revilla M, Obach V, et al. The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis 2005 Feb; 19(2): 91–5

    Article  PubMed  CAS  Google Scholar 

  62. Harcos P, Laki J, Kiszel P, et al. Decreased frequency of the TNF2 allele of TNF-alpha −308 promoter polymorphism is associated with lacunar infarction. Cytokine 2006 Jan; 33(2): 100–5

    Article  PubMed  CAS  Google Scholar 

  63. Urn JY, Kim HM. Tumour necrosis factor alpha gene polymorphism is associated with cerebral infarction. Brain Res Mol Brain Res 2004 Mar; 122(1): 99–102

    Google Scholar 

  64. Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995 Nov; 26(5): 1235–41

    Article  PubMed  CAS  Google Scholar 

  65. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995 Feb; 75(6): 71–74B

    Article  Google Scholar 

  66. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003 Feb; 23(2): 168–75

    Article  PubMed  CAS  Google Scholar 

  67. Marsden PA, Heng HHQ, Scherer SW, et al. Structure and chromosomal localization of the human consitutive endothelial nitric oxide synthase gene. J Bio Chem 1993 Aug; 268(23): 17478–588

    CAS  Google Scholar 

  68. Rossi GP, Taddei S, Virdis A, et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 2003 Mar; 41(6): 938–45

    Article  PubMed  CAS  Google Scholar 

  69. Yoshimura M, Nakayama M, Shimasaki Y, et al. A T−786->C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility. Am J Cardiol 2000 Mar; 85(6): 710–4

    Article  PubMed  CAS  Google Scholar 

  70. Leeson CPM, Hingorani AD, Mullen MJ, et al. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res 2002 Jun; 90(11): 1153–8

    Article  PubMed  CAS  Google Scholar 

  71. Nakayama M, Yasue H, Yoshimura M, et al. T−786->C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999 Jun; 99(22): 2864–70

    Article  PubMed  CAS  Google Scholar 

  72. Sim AS, Wang J, Wilcken D, et al. Mspl polymorphism in the promoter of the human endothelial constitutive NO synthase gene in Australian Caucasian population [letter]. Mol Genet Metab 1998 Sep; 65(1): 62

    Article  PubMed  CAS  Google Scholar 

  73. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 2000 Aug; 70(4): 241–51

    Article  PubMed  CAS  Google Scholar 

  74. Poirier O, Mao C, Mallet C, et al. Polymorphisms of the endothelial nitric oxide synthase gene: no consistent association with myocardial infarction in the ECTIM study. Eur J Clin Invest 1999 Apr; 29(4): 284–90

    Article  PubMed  CAS  Google Scholar 

  75. Cai H, Wilcken DEL, Wang XL. The Glu-298 ->Asp (894G->T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. J Mol Med 1999 Jul; 77(6): 511–4

    Article  PubMed  CAS  Google Scholar 

  76. Veldman BA, Spiering W, Dowevendans PA, et al. The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide. J Hypertens 2002 Oct; 20(10): 2023–7

    Article  PubMed  CAS  Google Scholar 

  77. Tesauro M, Thompson WC, Rogliani P, et al. Intracellular processing of endothelial nitric oxide synthase idoforms associated with differences in severity of cardiopulmonary disease: cleavage of proteins with aspartate vs glutamate at position 298. Proc Natl Acad Sci U S A 2000 Mar; 97(6): 2832–5

    Article  PubMed  CAS  Google Scholar 

  78. McDonald DM, Alp NJ, Channon KM. Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells. Pharmacogenetics 2004 Dec; 14(12): 831–9

    Article  PubMed  CAS  Google Scholar 

  79. Fairchild TA, Fulton D, Fontana JT, et al. Acidic hydrolysis as a mechanism for the cleavage of the Glu298->Asp variant of human endothelial nitric-oxide synthase. J Biol Chem 2001 Jul; 276(28): 26674–9

    Article  PubMed  CAS  Google Scholar 

  80. Inoue A, Yanagisawa M, Takuwa Y, et al. The human preproendothelin-1 gene: complete nucleotide sequence and regulation of expression. J Biol Chem 1989 Sep; 264(25): 14954–9

    PubMed  CAS  Google Scholar 

  81. Barden AE, Herbison CE, Beilin LJ, et al. Association between the endothelin-1 gene Lys198Asn polymorphism, blood pressure, and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens 2001 Oct; 19(10): 1775–82

    Article  PubMed  CAS  Google Scholar 

  82. McKinley MJ, Albiston AL, Allen AM, et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003 Jun; 35(6): 901–18

    Article  PubMed  CAS  Google Scholar 

  83. Baltatu O, Bader M. Brain renin-angiotensin system: lessons from functional genomics. Neuroendocrinology 2003 Nov; 78(5): 253–9

    Article  PubMed  CAS  Google Scholar 

  84. Hassan A, Lansbury A, Catto AJ, et al. Angiotensin converting enzyme insertion/ deletion genotype is associated with leukoaraiosis in lacunar syndromes. J Neurol Neurosurg Psychiatry 2002 Mar; 72(3): 343–6

    Article  PubMed  CAS  Google Scholar 

  85. Amar K, Macgowan S, Wilcock G, et al. Are genetic factors important in the aetiology of leukoaraiosis? Results from a memory clinic population. Int J Geriatr Psychiatry 1998 Sep; 13(9): 585–90

    Article  PubMed  CAS  Google Scholar 

  86. van Rijn MJE, Bos MJ, Isaacs A, et al. Polymorphisms of the renin angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology. J Neurol Neurosurg Psychiatry 2007 Oct; 78(10): 1083–7

    Article  PubMed  Google Scholar 

  87. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995 May; 10(1): 111–3

    Article  PubMed  CAS  Google Scholar 

  88. Kilpatrick T, Matkovic Z, Davis S, et al. Hematologic abnormalities occur in both cortical and lacunar infarction. Stroke 1993 Dec; 24(12): 1945–50

    Article  PubMed  CAS  Google Scholar 

  89. Hart RG, Kanter MC. Hematologic disorders and ischemic stroke: a selective review. Stroke 1990 Aug; 21(8): 1111–21

    Article  PubMed  CAS  Google Scholar 

  90. Margaglione M, D’Andrea G, Giuliani N, et al. Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with Factor V Leiden. Arterioscler Thromb Vasc Biol 1999 Jul; 19(7): 1751–6

    Article  PubMed  CAS  Google Scholar 

  91. Lalouschek W, Schillinger M, Hsieh K, et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke 2005 Jul; 36(7): 1405–9

    Article  PubMed  Google Scholar 

  92. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993 Jun; 118(12): 956–63

    PubMed  CAS  Google Scholar 

  93. Qizilbash N, Jones L, Warlow C, et al. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ 1991; 303: 605–9

    Article  PubMed  CAS  Google Scholar 

  94. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984 Aug; 311(8): 501–5

    Article  PubMed  CAS  Google Scholar 

  95. Behaque I, Poirier O, Nicaud V, et al. Beta-fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: the ECTIM Study. Circulation 1996 Feb; 93(3): 440–9

    Article  Google Scholar 

  96. Scarabin PY, Bara L, Ricard S, et al. Genetic variation at the beta-fibrinogen locus in relation to fibrinogen concentrations and risk of myocardial infarction: the ECTIM study. Arterioscler Thromb Vasc Biol 1993 Jun; 13(6): 886–91

    Article  CAS  Google Scholar 

  97. Kessler C, Spitzer C, Stauske D, et al. The apolopoprotein E and beta-fibrinogen G/ A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vase Biol 1997 Nov; 17(11): 2880–4

    Article  CAS  Google Scholar 

  98. Matsuno H, Kozawa O, Niwa M, et al. Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury. Thromb Haemostat 1999; 81: 601–4

    CAS  Google Scholar 

  99. Meade TW, Ruddock V, Stirling Y, et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993 Oct; 342(8879): 1076–9

    Article  PubMed  CAS  Google Scholar 

  100. Ridker PM, Vaughan DE, Stamfer MJ, et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993 Apr; 341(8854): 1165–8

    Article  PubMed  CAS  Google Scholar 

  101. Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994 Apr; 343(8903): 940–3

    Article  PubMed  CAS  Google Scholar 

  102. Degen SJ, Rajput B, Reich E. The human tissue plasminogen activator gene. J Biol Chem 1986 May; 261(15): 6972–85

    PubMed  CAS  Google Scholar 

  103. Henderson BR, Sleigh MJ. TATA box-independent transcription of the human tissue plasminogen activator gene initiates within a sequence conserved in related genes. FEBS Lett 1992 Sep; 309(2): 130–4

    Article  PubMed  CAS  Google Scholar 

  104. Costa M, Shen Y, Maurer F, et al. Transcriptional regulation of the tissue-type plasminogen-activator gene in human endothelial cells: identification of nuclear factors that recognise functional elements in the tissue-type plasminogen-activator gene promoter. Eur J Biochem 1998 Nov; 258(1): 123–31

    Article  PubMed  CAS  Google Scholar 

  105. Ladenvall P, Wall U, Jern S, et al. Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo. Thromb Haemost 2000 Aug; 84(2): 150–5

    PubMed  CAS  Google Scholar 

  106. Ladenvall P, Nilsson S, Jood K, et al. Genetic variation of the human tissue-type plasminogen activator (tPA) locus: haplotypes and analysis of associated to plasma levels of tPA. Eur J Hum Genet 2003 Aug; 11(8): 603–10

    Article  PubMed  CAS  Google Scholar 

  107. Grau AJ, Aulmann M, Lichy C, et al. Increased cytokine release by leucocytes in survivors of stroke at young age. Eur J Clin Invest 2001 Nov; 31(11): 999–1006

    Article  PubMed  CAS  Google Scholar 

  108. Kis Z, Sas K, Gyulai Z, et al. Chronic infections and genetic factors in the development of ischaemic stroke. New Microbiol 2007 Jul; 30(3): 213–20

    PubMed  CAS  Google Scholar 

  109. Fassbender K, Rossol S, Kammer T, et al. Proinflammatory cytokines in serum of patients with acute cerebral ischaemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci 1994 Apr; 122(2): 135–9

    Article  PubMed  CAS  Google Scholar 

  110. Tarkowski E, Rosengren L, Blomstrand C, et al. Early intrathecal production of interleukin-6 predicts the volume of brain lesion in stroke. Stroke 1995 Aug; 26(8): 1393–8

    Article  PubMed  CAS  Google Scholar 

  111. Vila N, Filella X, Deulofeu R, et al. Cytokine-induced inflammation and long-term stroke functional outcome. J Neuro Sci 1999 Jan; 162(2): 185–8

    Article  CAS  Google Scholar 

  112. Ray A, LaForge KS, Sehgal PB. On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Mol Cell Biol 1990 Nov; 10(11): 5736–46

    PubMed  CAS  Google Scholar 

  113. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998 Oct; 102(7): 1369–76

    Article  PubMed  CAS  Google Scholar 

  114. Tanabe O, Akira S, Kamiya T, et al. Genomic structure of the murine IL-6 gene: high degree conservation of potential regulatory sequences between mouse and human. J Immunol 1988 Dec; 141(11): 3875–81

    PubMed  CAS  Google Scholar 

  115. Revilla M, Obach V, Cervera A, et al. A −174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. Neurosci Lett 2002 May; 324(1): 29–32

    Article  PubMed  CAS  Google Scholar 

  116. Wilson AG, Symons JA, McDowell TL, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997 Apr; 94(7): 3195–9

    Article  PubMed  CAS  Google Scholar 

  117. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007 Aug; 357(5): 443–53

    Article  PubMed  CAS  Google Scholar 

  118. Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007 Aug; 357(8): 775–88

    Article  PubMed  CAS  Google Scholar 

  119. The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007 Aug; 357(9): 851–62

    Article  Google Scholar 

  120. Ross OA, Worrall BB, Meschia JF. Advancing stroke therapeutics through genetic understanding. Curr Drug Targets 2007 Jul; 8(7): 850–9

    Article  PubMed  CAS  Google Scholar 

  121. Kang CP, Lee KW, Yoo DH, et al. The influence of a polymorphism at position −857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology 2005 Apr; 44(4): 547–52

    Article  PubMed  CAS  Google Scholar 

  122. Mugnier B, Balandraud N, Darque A, et al. Polymorphism at position −308 of the tumor necrosis factor alpha influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003 Jul; 48(7): 1849–52

    Article  PubMed  CAS  Google Scholar 

  123. Padyukov L, Lampa J, Heimburger M, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003 Jun; 62(6): 526–9

    Article  PubMed  CAS  Google Scholar 

  124. Australian Government, Department of Health and Ageing. Schedule of pharmaceutical benefits [online]. Available from URL: http://www.pbs.gov.au/html/healthpro/home [Accessed 2007 Sep 5]

  125. Ooboshi H, Toyoda K, Faraci FM, et al. Improvement of relaxation in an atherosclerotic artery by gene transfer of endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol 1998 Nov; 18(11): 1752–8

    Article  PubMed  CAS  Google Scholar 

  126. Teupe C, Richter S, Fisslthaler B, et al. Vascular gene transfer of phosphomimetic endothelial nitric oxide synthase (S1177D) using ultrasound-enhanced destruction of plasmid-loaded microbubbles improves vasoreactivity. Circulation 2002 Mar; 105(9): 1104–9

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No funding was provided for the preparation of this review, and the authors have no conflicts of interest relevant to its content.

The authors would like to acknowledge the Departments of Neurology and Medicine, The Queen Elizabeth Hospital Research Foundation, and the University of Adelaide for their support.

Author information

Authors and Affiliations

  1. School of Medicine, University of Adelaide, The Queen Elizabeth Hospital Campus, Stroke Research Programme, 28 Woodville Rd, Woodville South, South Australia, 5011, Australia

    Ada Lam &  Simon A. Koblar

  2. Stroke Research Programme Department of Neurology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia

    M. Anne Hamilton-Bruce & Jim Jannes

Authors
  1. Ada Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Anne Hamilton-Bruce
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jim Jannes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon A. Koblar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simon A. Koblar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lam, A., Hamilton-Bruce, M.A., Jannes, J. et al. Cerebral Small Vessel Disease. Mol Diag Ther 12, 145–156 (2008). https://doi.org/10.1007/BF03256279

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256279

Keywords

Search

Navigation