title: Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants.
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.
authors.affiliation: Imperial College Cerebrovascular Research Unit, Clinical Neurosciences, Charing Cross Hospital, Imperial College London, London, United Kingdom. p.bentley@imperial.ac.uk
authors.forename: Paul
authors.initials: P
authors.lastname: Bentley
authors.forename: George
authors.initials: G
authors.lastname: Peck
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
mesh_terms: D019731:Carbon-Nitrogen Ligases / Q000235:genetics; D015984:Causality; D005165:Factor V / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017202:Myocardial Ischemia / Q000097:blood / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics; D011110:Polymorphism, Genetic; D011516:Prothrombin / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000235:genetics*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase