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

• Published in: PloS one Vol. 5; no. 2; p. e9136
• Main Authors: Bentley, Paul, Peck, George, Smeeth, Liam, Whittaker, John, Sharma, Pankaj
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.02.2010; Public Library of Science (PLoS)
• Subjects: Activated protein C; Analysis; Angiotensinogen; Angiotensins; Antigens; Biochemistry; Carbon-Nitrogen Ligases - genetics; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Disorders; Cardiovascular Disorders/Hypertension; Cardiovascular Disorders/Peripheral Vascular Disease; Causality; Clinical trials; Coagulation factors; Coronary artery disease; Disease susceptibility; Epidemiology; Equivalence; Factor V; Factor V - genetics; Genes; Genetic analysis; Genetic aspects; Genetic polymorphisms; Genetic Predisposition to Disease - genetics; Genotype; Glycoproteins; Health risks; Heart; Heart attacks; Heart diseases; Homocysteine; Hospitals; Humans; Ischemia; Medical research; Meta-analysis; Methylenetetrahydrofolate reductase; Myocardial ischemia; Myocardial Ischemia - blood; Myocardial Ischemia - genetics; Neurological Disorders/Cerebrovascular Disease; Neurological Disorders/Neurogenetics; Neurosciences; Odds Ratio; Phenotype; Plasma levels; Plasminogen Activator Inhibitor 1 - blood; Plasminogen Activator Inhibitor 1 - genetics; Polymorphism; Polymorphism, Genetic; Protein C; Prothrombin; Prothrombin - genetics; Risk Factors; Sample variance; Stroke; Stroke - blood; Stroke - genetics; Studies; Task forces; Thrombin; United Kingdom > UK; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009136

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.