IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0009136.html
   My bibliography  Save this article

Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants

Author

Listed:
  • Paul Bentley
  • George Peck
  • Liam Smeeth
  • John Whittaker
  • Pankaj Sharma

Abstract

Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 – 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes—glycoprotein IIIa, PAI-1 and angiotensinogen—show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.

Suggested Citation

  • Paul Bentley & George Peck & Liam Smeeth & John Whittaker & Pankaj Sharma, 2010. "Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants," PLOS ONE, Public Library of Science, vol. 5(2), pages 1-15, February.
    • Handle: RePEc:plo:pone00:0009136
    DOI: 10.1371/journal.pone.0009136
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009136
    Download Restriction: no
    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0009136&type=printable
    Download Restriction: no
    File URL: https://libkey.io/10.1371/journal.pone.0009136?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Roshan Ariyaratnam & Juan P Casas & John Whittaker & Liam Smeeth & Aroon D Hingorani & Pankaj Sharma, 2007. "Genetics of Ischaemic Stroke among Persons of Non-European Descent: A Meta-Analysis of Eight Genes Involving ∼ 32,500 Individuals," PLOS Medicine, Public Library of Science, vol. 4(4), pages 1-9, April.
    2. George Peck & Liam Smeeth & John Whittaker & Juan Pablo Casas & Aroon Hingorani & Pankaj Sharma, 2008. "The Genetics of Primary Haemorrhagic Stroke, Subarachnoid Haemorrhage and Ruptured Intracranial Aneurysms in Adults," PLOS ONE, Public Library of Science, vol. 3(11), pages 1-12, November.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Zhao-Feng Chen & Lufei Young & Chong Ho Yu & S. Pamela K. Shiao, 2018. "A Meta-Prediction of Methylenetetrahydrofolate-Reductase Polymorphisms and Air Pollution Increased the Risk of Ischemic Heart Diseases Worldwide," IJERPH, MDPI, vol. 15(7), pages 1-16, July.
    2. Christopher N Floyd & Benjamin H Ellis & Albert Ferro, 2014. "The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-8, July.
    3. Sunaina Yadav & Nazeeha Hasan & Thomas Marjot & Muhammad S Khan & Kameshwar Prasad & Paul Bentley & Pankaj Sharma, 2013. "Detailed Analysis of Gene Polymorphisms Associated with Ischemic Stroke in South Asians," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-8, March.
    4. Zhizhong Zhang & Gelin Xu & Dezhi Liu & Xinying Fan & Wusheng Zhu & Xinfeng Liu, 2012. "Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Contributes to Ischemic Stroke Risk: A Meta-Analysis of 50 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-9, October.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yuhao Sun & Ye Liu & Lora Talley Watts & Qingfang Sun & Zhihong Zhong & Guo-Yuan Yang & Liuguan Bian, 2013. "Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-8, June.
    2. George Peck & Liam Smeeth & John Whittaker & Juan Pablo Casas & Aroon Hingorani & Pankaj Sharma, 2008. "The Genetics of Primary Haemorrhagic Stroke, Subarachnoid Haemorrhage and Ruptured Intracranial Aneurysms in Adults," PLOS ONE, Public Library of Science, vol. 3(11), pages 1-12, November.
    3. Zhizhong Zhang & Gelin Xu & Dezhi Liu & Xinying Fan & Wusheng Zhu & Xinfeng Liu, 2012. "Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Contributes to Ischemic Stroke Risk: A Meta-Analysis of 50 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-9, October.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pone00:0009136. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.