Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke

Abstract

Purpose: Recent meta-analyses of genome-wide association studies (GWASs) have identified various genes and loci that confer susceptibility to coronary artery disease (CAD) or myocardial infarction (MI) in Caucasian populations. Among these genes and loci, some of the genetic variants that were originally detected to affect a risk of CAD were also related to ischemic stroke, suggesting a shared genetic architecture. Although CAD and ischemic stroke have been suggested to share genetic factors in Caucasian populations, the genes that confer susceptibility to both conditions in Japanese individuals have not been identified definitively. The purpose of the present study was to examine the possible association of ischemic stroke in Japanese individuals with 29 polymorphisms previously identified as susceptibility loci for CAD or MI by the meta-analyses of GWASs in Caucasian populations. Methods: The study population comprised 3187 Japanese individuals, including 894 subjects with ischemic stroke (atherothrombotic cerebral infarction) and 2293 controls. Subjects with cardiogenic embolic infarction, lacunar infarction alone, transient ischemic attack, moyamoya disease, cerebral venous sinus thrombosis, or traumatic cerebrovascular diseases were excluded from the study. The control individuals had no history of CAD, aortic aneurysm, or peripheral artery disease; of ischemic or hemorrhagic stroke or other cerebrovascular diseases. The genotypes for 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Results: Comparisons of allele frequencies by the chi-square test between subjects with ischemic stroke and controls revealed that rs9319428 (G->A) of the fms-related tyrosine kinase 1 gene (FLT1, P=0.0475), rs2075650 (G->A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0095), and rs273909 (T->C) of the solute carrier family 22 (organic cation transporter), member 4 gene (SLC22A4, P=0.0069) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; odds ratio, 0.50; recessive model) and rs273909 of SLC22A4 (P=0.0123; odds ratio, 0.45; dominant model) were significantly associated with ischemic stroke, with the minor G and C alleles, respectively, being protective against this condition. Conclusions: TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.