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Genetics of Carotid Disease

  • Bradford B. Worrall
  • Andrew M. Southerland
  • Keith L. Keene
Chapter

Abstract

The development of carotid atheroma results in stenosis, which has been shown to increase the risk of ischemic stroke. This chapter summarizes cerebrovascular atherosclerotic phenotypes and the genetic behind those phenotypes.

Keywords

Ischemic Stroke Carotid Plaque Carotid Artery Stenting Carotid Atherosclerosis Carotid Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46–215.PubMedCrossRefGoogle Scholar
  2. 2.
    Roger VrL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics‚ 2011 update/1. About 1. About these statistics/2. American Heart Association’s 2020 impact goals/3. Cardiovascular diseases/4. Subclinical atherosclerosis/5. Coronary heart disease, acute coronary syndrome, and angina pectoris/6. Stroke (cerebrovascular disease)/7. High blood pressure/8. Congenital cardiovascular defects/9. Cardiomyopathy and heart failure/10. Other cardiovascular diseases/11. Family history and genetics/12. Risk factor: smoking/tobacco use/13. Risk factor: high blood cholesterol and other lipids/14. Risk factor: physical inactivity/15. Risk factor: overweight and obesity/16. Risk factor: diabetes mellitus/17. End-stage renal disease and chronic kidney disease/18. Metabolic syndrome/19. Nutrition/20. Quality of care/21. Medical procedures/22. Economic cost of cardiovascular disease/23. At-a-glance summary tables/24. Glossary. Circulation. 2011;123(4):e18–209.PubMedCrossRefGoogle Scholar
  3. 3.
    Woo D, Gebel J, Miller R, Kothari R, Brott T, Khoury J, et al. Incidence rates of first-ever ischemic stroke subtypes among blacks: a population-based study. Stroke. 1999;30(12):2517–22.PubMedCrossRefGoogle Scholar
  4. 4.
    Palm F, Urbanek C, Wolf J, Buggle F, Kleemann T, Hennerici MG, et al. Etiology, risk factors and sex differences in ischemic stroke in the Ludwigshafen stroke study, a population-based stroke registry. Cerebrovasc Dis. 2012;33(1):69–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Hajat C, Heuschmann PU, Coshall C, Padayachee S, Chambers J, Rudd AG, et al. Incidence of aetiological subtypes of stroke in a multi-ethnic population based study: the South London Stroke Register. J Neurol Neurosurg Psychiatry. 2011;82(5):527–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology. 2004;62(4):569–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Roquer J, Campello AR, Gomis M. Sex differences in first-ever acute stroke. Stroke. 2003;34(7):1581–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Bejot Y, Caillier M, Ben Salem D, Couvreur G, Rouaud O, Osseby GV, et al. Ischaemic stroke subtypes and associated risk factors: a French population based study. J Neurol Neurosurg Psychiatry. 2008;79(12):1344–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Rincon F, Sacco RL, Kranwinkel G, Xu Q, Paik MC, Boden-Albala B, et al. Incidence and risk factors of intracranial atherosclerotic stroke: the Northern Manhattan Stroke Study. Cerebrovasc Dis. 2009;28(1):65–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Markus HS, Khan U, Birns J, Evans A, Kalra L, Rudd AG, et al. Differences in stroke subtypes between black and white patients with stroke: the South London Ethnicity and Stroke Study. Circulation. 2007;116(19):2157–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Ohira T, Shahar E, Chambless LE, Rosamond WD, Mosley Jr TH, Folsom AR. Risk factors for ischemic stroke subtypes: the Atherosclerosis Risk in Communities Study. Stroke. 2006;37(10):2493–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Li H, Wong KS. Racial distribution of intracranial and extracranial atherosclerosis. J Clin Neurosci. 2003;10(1):30–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke. 1996;27(11):1974–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Mak W, Cheng TS, Chan KH, Cheung RT, Ho SL. A possible explanation for the racial difference in distribution of large-arterial cerebrovascular disease: ancestral European settlers evolved genetic resistance to atherosclerosis, but confined to the intracranial arteries. Med Hypotheses. 2005;65(4):637–48.PubMedCrossRefGoogle Scholar
  16. 16.
    Putaala J, Curtze S, Hiltunen S, Tolppanen H, Kaste M, Tatlisumak T. Causes of death and predictors of 5-year mortality in young adults after first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke. 2009;40(8):2698–703.PubMedCrossRefGoogle Scholar
  17. 17.
    Purroy F, Montaner J, Molina CA, Delgado P, Ribo M, Alvarez-Sabin J. Patterns and predictors of early risk of recurrence after transient ischemic attack with respect to etiologic subtypes. Stroke. 2007;38(12):3225–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1998;339(20):1415–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1991;325(7):445–53.Google Scholar
  20. 20.
    Rerkasem K, Rothwell PM. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database Syst Rev. 2011;(4):CD001081.Google Scholar
  21. 21.
    Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev. 2005;(4):CD001923.Google Scholar
  22. 22.
    Voeks JH, Howard G, Roubin GS, Malas MB, Cohen DJ, Sternbergh 3rd WC, et al. Age and outcomes after carotid stenting and endarterectomy: the carotid revascularization endarterectomy versus stenting trial. Stroke. 2011;42(12):3484–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Howard VJ, Lutsep HL, Mackey A, Demaerschalk BM, Sam 2nd AD, Gonzales NR, et al. Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the carotid revascularization endarterectomy versus stenting trial (CREST). Lancet Neurol. 2011;10(6):530–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Brott TG, Hobson 2nd RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363(1):11–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Goodney PP, Travis LL, Malenka D, Bronner KK, Lucas FL, Cronenwett JL, et al. Regional variation in carotid artery stenting and endarterectomy in the Medicare population. Circ Cardiovasc Qual Outcomes. 2010;3(1):15–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Rudarakanchana N, Dialynas M, Halliday A. Asymptomatic carotid surgery trial-2 (ACST-2): rationale for a randomised clinical trial comparing carotid endarterectomy with carotid artery stenting in patients with asymptomatic carotid artery stenosis. Eur J Vasc Endovasc Surg. 2009;38(2):239–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Halliday AW, Lees T, Kamugasha D, Grant R, Hoffman A, Rothwell PM, et al. Waiting times for carotid endarterectomy in UK: observational study. BMJ. 2009;338:b1847.PubMedCrossRefGoogle Scholar
  28. 28.
    Halm EA. The good, the bad, and the about-to-get ugly: national trends in carotid revascularization: comment on “geographic variation in carotid revascularization among Medicare beneficiaries, 2003–2006”. Arch Intern Med. 2010;170(14):1225–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Berkowitz SA, Redberg RF. Dramatic increases in carotid stenting despite nonconclusive data. Arch Intern Med. 2011;171(20):1794–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Curtis LH, Greiner MA, Patel MR, Duncan PW, Schulman KA, Matchar DB. Geographic variation and trends in carotid imaging among medicare beneficiaries, 2001 to 2006. Circ Cardiovasc Qual Outcomes. 2010;3(6):599–606.PubMedCrossRefGoogle Scholar
  31. 31.
    Patel MR, Greiner MA, DiMartino LD, Schulman KA, Duncan PW, Matchar DB, et al. Geographic variation in carotid revascularization among Medicare beneficiaries, 2003–2006. Arch Intern Med. 2010;170(14):1218–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Duggirala R, Gonzalez Villalpando C, O’Leary DH, Stern MP, Blangero J. Genetic basis of variation in carotid artery wall thickness. Stroke. 1996;27(5):833–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Fox CS, Polak JF, Chazaro I, Cupples A, Wolf PA, D’Agostino RA, et al. Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study. Stroke. 2003;34(2):397–401.PubMedCrossRefGoogle Scholar
  34. 34.
    Fox CS, Cupples LA, Chazaro I, Polak JF, Wolf PA, D’Agostino RB, et al. Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. Am J Hum Genet. 2004;74(2):253–61.PubMedCrossRefGoogle Scholar
  35. 35.
    Naj AC, West M, Rich SS, Post W, Kao WH, Wasserman BA, et al. Association of scavenger receptor class B type I polymorphisms with subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Genet. 2010;3(1):47–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Iwata E, Yamamoto I, Motomura T, Tsubakimori S, Nohnen S, Ohmoto M, et al. The association of Pro12Ala polymorphism in PPARgamma2 with lower carotid artery IMT in Japanese. Diabetes Res Clin Pract. 2003;62(1):55–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Al-Shali KZ, House AA, Hanley AJ, Khan HM, Harris SB, Zinman B, et al. Genetic variation in PPARG encoding peroxisome proliferator-activated receptor gamma associated with carotid atherosclerosis. Stroke. 2004;35(9):2036–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Temelkova-Kurktschiev T, Hanefeld M, Chinetti G, Zawadzki C, Haulon S, Kubaszek A, et al. Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma2 protects against atherosclerosis. J Clin Endocrinol Metab. 2004;89(9):4238–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee BC, Lee HJ, Chung JH. Peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism is associated with reduced risk for ischemic stroke with type 2 diabetes. Neurosci Lett. 2006;410(2):141–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Zafarmand MH, van der Schouw YT, Grobbee DE, de Leeuw PW, Bots ML. Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: a case-cohort study and meta-analyses. Vasc Health Risk Manag. 2008;4(2):427–36.PubMedGoogle Scholar
  41. 41.
    Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, et al. Effect of the toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med. 2005;258(1):21–7.PubMedCrossRefGoogle Scholar
  42. 42.
    O’Donnell CJ, Cupples LA, D’Agostino RB, Fox CS, Hoffmann U, Hwang SJ, et al. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1:S4.PubMedCrossRefGoogle Scholar
  43. 43.
    Bis JC, Kavousi M, Franceschini N, Isaacs A, Abecasis GR, Schminke U, et al. Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. Nat Genet. 2011;43(10):940–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke. 1993;24(1):35–41.PubMedCrossRefGoogle Scholar
  45. 45.
    Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: the causative classification of stroke system. Stroke. 2007;38(11):2979–84.PubMedCrossRefGoogle Scholar
  46. 46.
    Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, et al. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. 2002;70(3):593–603.PubMedCrossRefGoogle Scholar
  47. 47.
    Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003;35(2):131–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Worrall BB, Mychaleckyj JC. PDE4D and stroke: a real advance or a case of the Emperor’s new clothes? Stroke. 2006;37(8):1955–7.PubMedCrossRefGoogle Scholar
  49. 49.
    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(10):1091–2. author reply 2–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004;36(3):233–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Burdon KP, Rudock ME, Lehtinen AB, Langefeld CD, Bowden DW, Register TC, et al. Human lipoxygenase pathway gene variation and association with markers of subclinical atherosclerosis in the diabetes heart study. Mediators Inflamm. 2010;2010:170153.PubMedCrossRefGoogle Scholar
  52. 52.
    Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, et al. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci USA. 2006;103(21):8161–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Domingues-Montanari S, Fernandez-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H, et al. Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case–control, meta-analysis and functional study. Cerebrovasc Dis. 2010;29(6):528–37.PubMedCrossRefGoogle Scholar
  54. 54.
    Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350(1):29–37.PubMedCrossRefGoogle Scholar
  55. 55.
    Roberts R, Stewart AF. 9p21 and the genetic revolution for coronary artery disease. Clin Chem. 2012;58(1):104–12.PubMedCrossRefGoogle Scholar
  56. 56.
    Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316(5830):1491–3.PubMedCrossRefGoogle Scholar
  57. 57.
    Samani NJ, Raitakari OT, Sipila K, Tobin MD, Schunkert H, Juonala M, et al. Coronary artery disease-associated locus on chromosome 9p21 and early markers of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28(9):1679–83.PubMedCrossRefGoogle Scholar
  58. 58.
    McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316(5830):1488–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.CrossRefGoogle Scholar
  60. 60.
    Scheffold T, Kullmann S, Huge A, Binner P, Ochs HR, Schols W, et al. Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry. BMC Cardiovasc Disord. 2011;11:9.PubMedCrossRefGoogle Scholar
  61. 61.
    Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet. 2010;6(4):e1000899.PubMedCrossRefGoogle Scholar
  62. 62.
    Dandona S, Stewart AF, Roberts R. Genomics in coronary artery disease: past, present and future. Can J Cardiol. 2010;26(Suppl A):56A–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Mohlke KL, et al. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One. 2009;4(4):e5027.PubMedCrossRefGoogle Scholar
  64. 64.
    Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol. 2012;32(2):196–206.PubMedCrossRefGoogle Scholar
  65. 65.
    Folkersen L, Kyriakou T, Goel A, Peden J, Malarstig A, Paulsson-Berne G, et al. Relationship between CAD risk genotype in the chromosome 9p21 locus and gene expression. Identification of eight new ANRIL splice variants. PLoS One. 2009;4(11):e7677.PubMedCrossRefGoogle Scholar
  66. 66.
    Congrains A, Kamide K, Oguro R, Yasuda O, Miyata K, Yamamoto E, et al. Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis. 2012;220:449–55.PubMedCrossRefGoogle Scholar
  67. 67.
    Matarin M, Brown WM, Singleton A, Hardy JA, Meschia JF. Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21. Stroke. 2008;39(5):1586–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Ye S, Willeit J, Kronenberg F, Xu Q, Kiechl S. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol. 2008;52(5):378–84.PubMedCrossRefGoogle Scholar
  69. 69.
    Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H, et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009;65(5):531–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Anderson CD, Biffi A, Rost NS, Cortellini L, Furie KL, Rosand J. Chromosome 9p21 in ischemic stroke: population structure and meta-analysis. Stroke. 2010;41(6):1123–31.PubMedCrossRefGoogle Scholar
  71. 71.
    Olsson S, Jood K, Blomstrand C, Jern C. Genetic variation on chromosome 9p21 shows association with the ischaemic stroke subtype large-vessel disease in a Swedish sample aged </= 70. Eur J Neurol. 2011;18(2):365–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Lin HF, Tsai PC, Liao YC, Lin TH, Tai CT, Juo SH, et al. Chromosome 9p21 genetic variants are associated with myocardial infarction but not with ischemic stroke in a Taiwanese population. J Investig Med. 2011;59(6):926–30.PubMedGoogle Scholar
  73. 73.
    Plant SR, Samsa GP, Shah SH, Goldstein LB. Exploration of a hypothesized independent association of a common 9p21.3 gene variant and ischemic stroke in patients with and without angiographic coronary artery disease. Cerebrovasc Dis. 2011;31(2):117–22.PubMedCrossRefGoogle Scholar
  74. 74.
    Nambi V, Boerwinkle E, Lawson K, Brautbar A, Chambless L, Franeschini N, et al. The 9p21 genetic variant is additive to carotid intima media thickness and plaque in improving coronary heart disease risk prediction in white participants of the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2012;222:135–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Dutta A, Henley W, Lang IA, Murray A, Guralnik J, Wallace RB, et al. The coronary artery disease-associated 9p21 variant and later life 20-year survival to cohort extinction. Circ Cardiovasc Genet. 2011;4(5):542–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Palomaki GE, Melillo S, Neveux L, Douglas MP, Dotson WD, Janssens AC, et al. Use of genomic profiling to assess risk for cardiovascular disease and identify individualized prevention strategies–a targeted evidence-based review. Genet Med. 2010;12(12):772–84.PubMedCrossRefGoogle Scholar
  77. 77.
    Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: Genomic profiling to assess cardiovascular risk to improve cardiovascular health. Genet Med. 2010;12(12):839–43.Google Scholar
  78. 78.
    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;44:328–33.PubMedCrossRefGoogle Scholar
  79. 79.
    Yan K, Cao Q, Reilly CM, Young NL, Garcia BA, Mishra N. Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J Biol Chem. 2011;286(33):28833–43.PubMedCrossRefGoogle Scholar
  80. 80.
    Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10(1):32–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Tayo BO, Luke A, Zhu X, Adeyemo A, Cooper RS. Association of regions on chromosomes 6 and 7 with blood pressure in Nigerian families. Circ Cardiovasc Genet. 2009;2(1):38–45.PubMedCrossRefGoogle Scholar
  82. 82.
    Zhang X, Chen HM, Jaramillo E, Wang L, D’Mello SR. Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction. J Neurosci Res. 2008;86(11):2423–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Lv L, Tang YP, Han X, Wang X, Dong Q. Therapeutic application of histone deacetylase inhibitors for stroke. Cent Nerv Syst Agents Med Chem. 2011;11(2):138–49.PubMedGoogle Scholar
  84. 84.
    Langley B, Brochier C, Rivieccio MA. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke. 2009;40(8):2899–905.PubMedCrossRefGoogle Scholar
  85. 85.
    Holliday EG, Maguire JM, Evans T-J, Golledge J, Biros E, Lewis MD, et al. A locus on chromosome 6p21.1 is associated with large artery atherosclerotic stroke (abstract). In: International stroke conference, New Orleans, 2012.Google Scholar
  86. 86.
    Holliday EG, Maguire JM, Evans T-J, Koblar S, Jannes J, Sturm JW, et al. A locus on chromosome 6p21.1 is associated with large artery atherosclerotic stroke. Nat Genet. 2012 (in press).Google Scholar
  87. 87.
    Gertow K, Nobili E, Folkersen L, Newman JW, Pedersen TL, Ekstrand J, et al. 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms. Atherosclerosis. 2011;215(2):411–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Chowdhury M, Ghosh J, Slevin M, Smyth JV, Alexander MY, Serracino-Inglott F. A comparative study of carotid atherosclerotic plaque microvessel density and angiogenic growth factor expression in symptomatic versus asymptomatic patients. Eur J Vasc Endovasc Surg. 2010;39(4):388–95.PubMedCrossRefGoogle Scholar
  89. 89.
    Stamova B, Xu H, Jickling G, Bushnell C, Tian Y, Ander BP, et al. Gene expression profiling of blood for the prediction of ischemic stroke. Stroke. 2010;41(10):2171–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhan X, Jickling GC, Tian Y, Stamova B, Xu H, Ander BP, et al. Transient ischemic attacks characterized by RNA profiles in blood. Neurology. 2011;77(19):1718–24.PubMedCrossRefGoogle Scholar
  91. 91.
    Jickling GC, Zhan X, Stamova B, Ander BP, Tian Y, Liu D, et al. Ischemic transient neurological events identified by immune response to cerebral ischemia. Stroke. 2012;43:1006–12.PubMedCrossRefGoogle Scholar
  92. 92.
    Xu H, Tang Y, Liu DZ, Ran R, Ander BP, Apperson M, et al. Gene expression in peripheral blood differs after cardioembolic compared with large-vessel atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. J Cereb Blood Flow Metab. 2008;28(7):1320–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Jickling GC, Xu H, Stamova B, Ander BP, Zhan X, Tian Y, et al. Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010;68(5):681–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • Bradford B. Worrall
    • 1
  • Andrew M. Southerland
    • 2
  • Keith L. Keene
    • 3
  1. 1.Department of NeurologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of NeurologyUniversity of Virginia Health SystemsCharlottesvilleUSA
  3. 3.Department of Biochemistry and Molecular GeneticsUniversity of VirginiaCharlottesvilleUSA

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