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

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  • 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.

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  • 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
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    References listed on IDEAS

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    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.
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    1. 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.
    2. 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.
    3. 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.
    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.

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