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Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants.

Title: Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants.
Authors: Bentley, P
Peck, G
Smeeth, L
Whittaker, J
Sharma, P
Item Type: Journal Article
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.
Issue Date: Feb-2010
Date of Acceptance: 4-Jan-2010
URI: http://hdl.handle.net/10044/1/79275
DOI: 10.1371/journal.pone.0009136
ISSN: 1932-6203
Publisher: Public Library of Science (PLoS)
Start Page: e9136(1)
End Page: e9136(15)
Journal / Book Title: PLoS One
Volume: 5
Issue: 2
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PLASMINOGEN-ACTIVATOR INHIBITOR
CORONARY-ARTERY-DISEASE
CARDIOVASCULAR-DISEASE
MYOCARDIAL-INFARCTION
PRIMARY PREVENTION
RISK
METAANALYSIS
POLYMORPHISM
ASSOCIATION
PLASMA
Carbon-Nitrogen Ligases
Causality
Factor V
Genetic Predisposition to Disease
Genotype
Humans
Myocardial Ischemia
Odds Ratio
Phenotype
Plasminogen Activator Inhibitor 1
Polymorphism, Genetic
Prothrombin
Risk Factors
Stroke
Humans
Myocardial Ischemia
Genetic Predisposition to Disease
Prothrombin
Carbon-Nitrogen Ligases
Factor V
Plasminogen Activator Inhibitor 1
Odds Ratio
Risk Factors
Causality
Genotype
Phenotype
Polymorphism, Genetic
Stroke
General Science & Technology
Edition: 5
Publication Status: Published
Online Publication Date: 2010-02-09
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine
Department of Brain Sciences



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