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Genetics of ischemic and hemorrhagic stroke in Chinese population

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Abstract

Stroke is a major cause of adult death and disability worldwide. Epidemiological and animal studies have provided strong evidence that the pathogenesis of stroke is multi-factorial and induced by a combination of environmental and genetic risk factors, but the identification of individual causative variants remains little known. Genetic influences are likely to be polygenic with small effect sizes, and stroke itself consists of a number of different subtypes which may each have different genetic profiles. In addition, various ethnic populations may have different stroke risk, such as Asian race. The reasons for high risk of stroke among the Chinese, especially hemorrhagic stroke, remain unknown. Most human studies have taken a candidate gene approach using case-control methodology. To be reliably detected, small relative risks require large sample sizes, probably 1000 patients or more. Genome-wide association (GWA) study is an unbiased and comprehensive approach to identify common risk alleles for complex diseases. Recently, a multistage GWA study has identified three loci on chromosomes 2q, 8q and 9p to be associated with intracranial aneurysm in European and Japanese populations. Another GWA finding is the identification of risk variants for cardioembolic stroke on chromosome 4q25 in European populations. In this review, we mainly focus on the results from case-control association studies on genetic factors that play a role in the risk of ischemic and hemorrhagic stroke in Chinese population. The combined effects of multiple susceptibility genes for stroke risk are also summarized.

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References

  1. Liu M, Wu B, Wang W Z, Lee L M, Zhang S H, Kong L Z. Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol, 2007, 6(5): 456–464

    Article  PubMed  Google Scholar 

  2. Reed D M. The paradox of high risk of stroke in populations with low risk of coronary heart disease. Am J Epidemiol, 1990, 131(4): 579–588

    CAS  PubMed  Google Scholar 

  3. Flossmann E, Schulz U G, Rothwell P M. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke, 2004, 35(1): 212–227

    Article  PubMed  Google Scholar 

  4. Adams H P Jr, Bendixen B H, Kappelle L J, Biller J, Love B B, Gordon D L. 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

    PubMed  Google Scholar 

  5. Schulz U G, Flossmann E, Rothwell P M. Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke, 2004, 35(4): 819–824

    Article  CAS  PubMed  Google Scholar 

  6. Jerrard-Dunne P, Cloud G, Hassan A, Markus H S. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke, 2003, 34(6): 1364–1369

    Article  PubMed  Google Scholar 

  7. Qureshi A I, Tuhrim S, Broderick J P, Batjer H H, Hondo H, Hanley D F. Spontaneous intracerebral hemorrhage. N Engl J Med, 2001, 344(19): 1450–1460

    Article  CAS  PubMed  Google Scholar 

  8. Healy D G. Case-control studies in the genomic era: a clinician’s guide. Lancet Neurol, 2006, 5(8): 701–707

    Article  CAS  PubMed  Google Scholar 

  9. Li Z, Sun L, Zhang H, Liao Y, Wang D, Zhao B, Zhu Z, Zhao J, Ma A, Han Y, Wang Y, Shi Y, Ye J, Hui R. 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, 34(9): 2085–2090

    Article  CAS  PubMed  Google Scholar 

  10. Wald D S, Law M, Morris J K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ, 2002, 325(7374): 1202

    Article  PubMed  Google Scholar 

  11. Kang S S, Zhou J, Wong P W, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet, 1988, 43(4): 414–421

    CAS  PubMed  Google Scholar 

  12. Morita H, Kurihara H, Tsubaki S, Sugiyama T, Hamada C, Kurihara Y, Shindo T, Oh-Hashi Y, Kitamura K, Yazaki Y. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol, 1998, 18(9): 1465–1469

    CAS  PubMed  Google Scholar 

  13. Zhang W, Sun K, Chen J, Liao Y, Qin Q, Ma A, Wang D, Zhu Z, Wang Y, Hui R. High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population. Clin Sci (Lond), 2010, 118(3): 187–194

    Article  CAS  Google Scholar 

  14. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet, 2007, 369(9576): 1876–1882

    Article  CAS  PubMed  Google Scholar 

  15. Zhao C X, Cui Y H, Fan Q, Wang P H, Hui R, Cianflone K, Wang D W. Small dense low-density lipoproteins and associated risk factors in patients with stroke. Cerebrovasc Dis, 2009, 27(1): 99–104

    Article  CAS  PubMed  Google Scholar 

  16. Brazier L, Tiret L, Luc G, Arveiler D, Ruidavets J B, Evans A, Chapman J, Cambien F, Thillet J. Sequence polymorphisms in the apolipoprotein(a) gene and their association with lipoprotein(a) levels and myocardial infarction: the ECTIM Study. Atherosclerosis, 1999, 144(2): 323–333

    Article  CAS  PubMed  Google Scholar 

  17. Peng D Q, Zhao S P, Wang J L. Lipoprotein(a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke. J Cardiovasc Risk, 1999, 6(1): 1–6

    CAS  PubMed  Google Scholar 

  18. Scholz M, Kraft H G, Lingenhel A, Delport R, Vorster E H, Bickeboller H, Utermann G. Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians. Eur J Hum Genet, 1999, 7(2): 169–178

    Article  CAS  PubMed  Google Scholar 

  19. Sandholzer C, Hallman D M, Saha N, Sigurdsson G, Lackner C, Csaszar A, Boerwinkle E, Utermann G. Effects of the apolipoprotein (a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet, 1991, 86(6): 607–614

    Article  CAS  PubMed  Google Scholar 

  20. Trommsdorff M, Kochl S, Lingenhel A, Kronenberg F, Delport R, Vermaak H, Lemming L, Klausen I C, Faergeman O, Utermann G. A pentanucleotide repeat polymorphism in the 5′ control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians. J Clin Invest, 1995, 96(1): 150–157

    Article  CAS  PubMed  Google Scholar 

  21. Sun L, Li Z, Zhang H, Ma A, Liao Y, Wang D, Zhao B, Zhu Z, Zhao J, Zhang Z, Wang W, Hui R. Pentanucleotide TTTTA repeat polymorphism of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese: a multicenter case-control study in China. Stroke, 2003, 34(7): 1617–1622

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Zhen Y, Shi Y, Chen J, Zhang C, Wang X, Yang X, Zheng Y, Liu Y, Hui R. Vitamin K epoxide reductase: a protein involved in angiogenesis. Mol Cancer Res, 2005, 3(6): 317–323

    Article  CAS  PubMed  Google Scholar 

  23. Rieder M J, Reiner A P, Gage B F, Nickerson D A, Eby C S, McLeod H L, Blough D K, Thummel K E, Veenstra D L, Rettie A E. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med, 2005, 352(22): 2285–2293

    Article  CAS  PubMed  Google Scholar 

  24. Wang Y, Zhang W, Zhang Y, Yang Y, Sun L, Hu S, Chen J, Zhang C, Zheng Y, Zhen Y, Sun K, Fu C, Yang T, Wang J, Sun J, Wu H, Glasgow W C, Hui R. VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation, 2006, 113(12): 1615–1621

    Article  PubMed  Google Scholar 

  25. Moulton K S. Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr Opin Lipidol, 2006, 17(5): 548–555

    Article  CAS  PubMed  Google Scholar 

  26. Celletti F L, Waugh J M, Amabile P G, Brendolan A, Hilfiker P R, Dake M D. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med, 2001, 7(4): 425–442

    Article  CAS  PubMed  Google Scholar 

  27. Cleaver O, Melton D A. Endothelial signaling during development. Nat Med, 2003, 9(6): 661–668

    Article  CAS  PubMed  Google Scholar 

  28. Zhang W, Sun K, Zhen Y, Wang D, Wang Y, Chen J, Xu J, Hu F B, Hui R. VEGF receptor-2 variants are associated with susceptibility to stroke and recurrence. Stroke, 2009, 40(8): 2720–2726

    Article  CAS  PubMed  Google Scholar 

  29. Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol, 2007, 50(8): 760–767

    Article  CAS  PubMed  Google Scholar 

  30. Chen J, Yu H, Song W, Sun K, Song Y, Lou K, Yang T, Zhang Y, Hui R. Angiopoietin-2 promoter haplotypes confer an increased risk of stroke in a Chinese Han population. Clin Sci (Lond), 2009, 117(11): 387–395

    Article  CAS  Google Scholar 

  31. Vallance P and Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol, 2004, 24(6): 1023–1030

    Article  CAS  PubMed  Google Scholar 

  32. Bai Y, Chen J, Sun K, Xin Y, Liu J, Hui R. Common genetic variation in DDAH2 is associated with intracerebral haemorrhage in a Chinese population: a multi-centre case-control study in China. Clin Sci (Lond), 2009, 117(7): 273–279

    Article  CAS  Google Scholar 

  33. Gretarsdottir S, Thorleifsson G, Reynisdottir S T, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir S M, Einarsson O B, Gudjonsdottir H M, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir A S, Sigurdardottir M, Chou T T, Nahmias J, Goss S, Sveinbjörnsdottir S, Valdimarsson E M, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge M L, Kong A, Stefansson K, Gulcher J R. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet, 2003, 35(2): 131–138

    Article  CAS  PubMed  Google Scholar 

  34. Song Q, Cole J W, O’Connell J R, Stine O C, Gallagher M, Giles W H, Mitchell B D, Wozniak M A, Stern B J, Sorkin J D, McArdle P F, Naj A C, Xu Q, Gibbons G H, Kittner S J. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the stroke prevention in young women study. Hum Mol Genet, 2006, 15(16): 2468–2478

    Article  CAS  PubMed  Google Scholar 

  35. Xue H, Wang H, Song X, Li W, Sun K, Zhang W, Wang X, Wang Y, Hui R. Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke. Clin Sci (Lond), 2009, 116(4): 335–340

    Article  CAS  Google Scholar 

  36. Helgadottir, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani N J, Gudmundsson G, Grant S F, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson E M, Matthiasson S E, Johannsson H, Gudmundsdottir O, Gurney M E, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge M L, Topol E J, Kong A, Gudnason V, Hakonarson H, Gulcher J R, Stefansson K. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet, 2004, 36(3): 233–239

    Article  CAS  PubMed  Google Scholar 

  37. Zhang W L, Yang X M, Shi J, Sun K, Hui R T. Polymorphism of SG13S114T/A in the ALOX5AP gene and the risk for stroke in a large Chinese cohort. Yi Chuan Xue Bao, 2006, 33(8): 678–684 (in Chinese)

    CAS  PubMed  Google Scholar 

  38. Wang Q, Ding H, Tang J R, Zhang L, Xu YJ, Yan JT, Wang W, Hui R T, Wang CY, Wang D W. C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population. Acta Pharmacol Sin, 2009, 30(3): 291–298

    Article  PubMed  Google Scholar 

  39. Song W, Chen J, Sun K, Yu H, Hui R. No association of PLIN polymorphisms with hemorrhagic and ischemic stroke. Stroke, 2008, 39(2): 470–472

    Article  PubMed  Google Scholar 

  40. Zhang L, Ding H, Yan J, Hui R, Wang W, Kissling G E, Zeldin D C, Wang D W. Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population. Pharmacogenet Genomics, 2008, 18(1): 45–51

    Article  PubMed  Google Scholar 

  41. Zhang L, Zhang H, Sun K, Song Y, Hui R, Huang X. The 825C/T polymorphism of G-protein beta3 subunit gene and risk of ischaemic stroke. J Hum Hypertens, 2005, 19(9): 709–714

    Article  CAS  PubMed  Google Scholar 

  42. Ritchie M D, Hahn L W, Roodi N, Bailey L R, Dupont W D, Parl F F, Moore J H. Multifactor-dimensionality reduction reveals high order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet, 2001, 69(1): 138–147

    Article  CAS  PubMed  Google Scholar 

  43. Shen C D, Zhang W L, Sun K, Wang Y B, Zhen Y S, Hui R T. Interaction of genetic risk factors confers higher risk for thrombotic stroke in male Chinese: a multicenter case-control study. Ann Hum Genet, 2007, 71(Pt 5): 620–629

    Article  CAS  PubMed  Google Scholar 

  44. Liu J, Sun K, Bai Y, Zhang W, Wang X, Wang Y, Wang H, Chen J, Song X, Xin Y, Liu Z, Hui R. Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study. Hum Genet, 2009, 125(5,6): 649–656

    Article  PubMed  Google Scholar 

  45. Bilguvar K, Yasuno K, Niemelä M, Ruigrok Y M, von Und Zu Fraunberg M, van Duijn C M, van den Berg L H, Mane S, Mason CE, Choi M, Gaál E, Bayri Y, Kolb L, Arlier Z, Ravuri S, Ronkainen A, Tajima A, Laakso A, Hata A, Kasuya H, Koivisto T, Rinne J, Ohman J, Breteler M M, Wijmenga C, State M W, Rinkel G J, Hernesniemi J, Jääskeläinen J E, Palotie A, Inoue I, Lifton R P, Günel M. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet, 2008, 40(12): 1472–1477

    Article  CAS  PubMed  Google Scholar 

  46. Helgadottir A, Thorleifsson G, Magnusson K P, Grétarsdottir S, Steinthorsdottir V, Manolescu A, Jones G T, Rinkel G J, Blankensteijn J D, Ronkainen A, Jääskeläinen J E, Kyo Y, Lenk G M, Sakalihasan N, Kostulas K, Gottsäter A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah S H, Quyyumi A A, Granger C B, Reilly M P, Austin H, Levey A I, Vaccarino V, Palsdottir E, Walters G B, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell R E, Sveinbjornsdottir S, Hernesniemi J, Niemelä M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven E L, Teijink J A, Grobbee D E, Rader D J, Collier D A, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson E M, Magnadottir H B, Wijmenga C, Tromp G, Baas A F, Ruigrok Y M, van Rij A M, Kuivaniemi H, Powell J T, Matthiasson S E, Gulcher J R, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet, 2008, 40(2): 217–224

    Article  CAS  PubMed  Google Scholar 

  47. Kim I, Saunders T L, Morrison S J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell, 2007, 130(3): 470–483

    Article  CAS  PubMed  Google Scholar 

  48. Janzen V, Forkert R, Fleming H E, Saito Y, Waring M T, Dombkowski D M, Cheng T, DePinho R A, Sharpless N E, Scadden D T. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature, 2006, 443(7110): 421–426

    CAS  PubMed  Google Scholar 

  49. Gretarsdottir S, Thorleifsson G, Manolescu A, Styrkarsdottir U, Helgadottir A, Gschwendtner A, Kostulas K, Kuhlenbäumer G, Bevan S, Jonsdottir T, Bjarnason H, Saemundsdottir J, Palsson S, Arnar D O, Holm H, Thorgeirsson G, Valdimarsson E M, Sveinbjörnsdottir S, Gieger C, Berger K, Wichmann H E, Hillert J, Markus H, Gulcher J R, Ringelstein E B, Kong A, Dichgans M, Gudbjartsson D F, Thorsteinsdottir U, Stefansson K. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol, 2008, 64(4): 402–409

    Article  PubMed  Google Scholar 

  50. Pollex R L, Hegele R A. Copy number variation in the human genome and its implications for cardiovascular disease. Circulation, 2007, 115(24): 3130–3138

    Article  PubMed  Google Scholar 

  51. Rieder M J, Reiner A P, Gage B F. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med, 2005, 352(22): 2285–2293

    Article  CAS  PubMed  Google Scholar 

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Zhang, WL., Hui, RT. Genetics of ischemic and hemorrhagic stroke in Chinese population. Front. Med. China 4, 21–28 (2010). https://doi.org/10.1007/s11684-010-0013-x

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