Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis Loo Keat Wei, PhD,* Anthony Au, MSc,† Saras Menon, PhD,‡ Lyn R. Griffiths, PhD,‡ Cheah Wee Kooi, FRCP,§ Looi Irene, FRCP,‖ Jiangyang Zhao, PhD,¶ Chaeyoung Lee, PhD,# Avdonina Maria Alekseevna, PhD,** Muhammad Radzi Abdul Hassan, MRCP,†† and Zariah Abdul Aziz, MBBS‡‡ Introduction: The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothe- lial nitric oxide synthase (eNOS; −786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin- converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic poly- morphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. Methods: All case-control studies published in dif- ferent languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger’s regression analyses were performed in this study. Results: A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS −786T>C polymorphisms are not associated with ischemic stroke risks. Conclusions: Hence, the evidence from this From the *Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, Kampar, Perak, Malaysia; †Department of Bioprocess Engineering, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, Skudai, Malaysia; ‡Genomics Re- search Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, MuskAvenue, Kelvin Grove, Queensland, Australia; §Department of Medicine and Clinical Research Centre, Taiping Hospital, Jalan Tamingsari, Taiping, Perak, Malaysia; ‖Department of Medicine and Clinical Research Centre, Hospital Seberang Jaya, Jalan Tun Hussein Onn, Seberang Jaya, Pulau Pinang, Malaysia; ¶Depart- ment of Clinical Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China; #School of Systems Biomedical Science, Soongsil University, 511 Sangdo-dong, Dongjak-gu, Seoul, Republic of Korea; **Laboratory of Biological Mi- crochips, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; ††Medical Department, Hospital Sultanah Bahiyah, Alor Star, Kedah, Malaysia; and ‡‡Neurology Division, Department of Medicine, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, Kuala Terengganu, Kuala Terengganu, Malaysia. Received May 1, 2017; revision received May 12, 2017; accepted May 17, 2017. Grant support: We acknowledge the support from the Ministry of Higher Education Fundamental Research Grant Scheme (FRGS/1/2015/ SKK08/UTAR/02/3) and Universiti Tunku Abdul Rahman under the UTAR Research Fund 6200/LF3. Address correspondence to Loo Keat Wei, PhD, Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, Kampar, Perak 31900, Malaysia. E-mail: wynnelkw@gmail.com. 1052-3057/$ - see front matter Crown Copyright © 2017 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.048 ARTICLE IN PRESS Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■ 1