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(Stroke. 2009;40:683.)
© 2009 American Heart Association, Inc.

Original Contributions

A Meta-Analysis of Candidate Gene Polymorphisms and Ischemic Stroke in 6 Study Populations

Association of Lymphotoxin-Alpha in Nonhypertensive Patients

Xingyu Wang, PhD; Suzanne Cheng, PhD; Victoria H. Brophy, PhD; Henry A. Erlich, PhD; Christine Mannhalter, PhD; Klaus Berger, MD; Wolfgang Lalouschek, MD; Warren S. Browner, MD; Yu Shi, MS; E. Bernd Ringelstein, MD; Christof Kessler, MD; Jan Luedemann, PhD; Klaus Lindpaintner, MD; Lisheng Liu, MD; Paul M. Ridker, MD; Robert Y.L. Zee, PhD; Nancy R. Cook, ScD for the RMS Stroke SNP Consortium

From the Laboratory of Human Genetics (X.W., Y.S., L.L.), Beijing Hypertension League Institute, Beijing, China.; the Department of Human Genetics (S.C., V.H.B., H.A.E.), Roche Molecular Systems, Inc., Pleasanton, Calif; the Department of Medical and Chemical Laboratory Diagnostics (C.M.) and the University Clinic of Neurology (W.L.), Medical University Vienna, Vienna, Austria; the Institute of Epidemiology and Social Medicine (K.B.) and Department of Neurology (E.B.R.), University of Muenster, Muenster, Germany; S.F. Coordinating Center (W.S.B.), California Pacific Medical Center, Research Institute, San Francisco, Calif; the Department of Neurology (C.K.) and the Institute of Clinical Chemistry and Laboratory Medicine (J.L.), Ernst Moritz Arndt University, Greifswald, Germany; Roche Center for Medical Genomics (K.L.), F. Hoffmann-La Roche, Ltd, Basel, Switzerland; and the Center for Cardiovascular Disease Prevention and Division of Preventive Medicine (P.M.R., R.Y.L.Z., N.R.C.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Nancy R. Cook, ScD, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail ncook{at}rics.bwh.harvard.edu

Background and Purpose— Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways, including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion, have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors.

Methods— We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 control subjects from 6 case–control association studies conducted in the United States, Europe, and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant, and recessive models of inheritance.

Results— Although 7 polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, 2 lymphotoxin-alpha polymorphisms, which are in strong linkage disequilibrium, were significantly associated among nonhypertensive individuals: LTA 252A>G (additive model; OR, 1.41 with 95% CI, 1.20 to 1.65; P=0.00002) and LTA 26Thr>Asn (OR, 1.19 with 95% CI, 1.06 to 1.34; P=0.003). LTA 252A>G remained significant after adjustment for multiple testing using either the false discovery rate or by permutation testing. The 2 single nucleotide polymorphisms showed no association in hypertensive subjects (eg, LTA 252A>G, OR, 0.93; 95% CI, 0.84 to 1.03; P=0.17).

Conclusions— These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.

Key Words: embolic stroke • genetics • hypertension • inflammation

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