Published Online
on April 10, 2008

A more recent version of this article appeared on June 1, 2008

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Submitted on October 14, 2007
Accepted on November 7, 2007

Polymorphisms in Platelet Glycoprotein 1b and Factor VII and Risk of Ischemic Stroke. A Meta-Analysis

Jane M. Maguire BA, BNurs (Hons)^*; Ammarin Thakkinstian PhD; Jon Sturm PhD; Christopher Levi MBBS; Lisa Lincz PhD; Mark Parsons PhD; Scott Whyte PhD; and John Attia PhD

From the University of Newcastle (J.M.M., J.S., C.L., M.P., S.W., J.A.), School of Medicine and Public Health, Faculty of Health, Callaghan, New South Wales, Australia; Hunter Medical Research Institute (J.M.M., C.L., L.L., M.P., J.A.), Newcastle, New South Wales, Australia; the Clinical Epidemiology Unit (A.T.), Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; the Centre for Clinical Epidemiology and Biostatistics (A.T., J.A.), University of Newcastle, Newcastle, New South Wales, Australia; the Hunter Haematology Research Group (L.L.), Calvary Mater Newcastle, Waratah, New South Wales, Australia; the Division of Medicine (C.L., M.P., J.A.), John Hunter Hospital, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; the University of Newcastle (J.M.M.), School of Biomedical Sciences, Faculty of Health, Callaghan, New South Wales, Australia; the Priority Research Centre for Brain and Mental Health Research (C.L., L.L., M.P., J.A.), Hunter Medical Research Institute/University of Newcastle, Stroke Research Group, Brain & Mental Health Research Program, New South Wales, Australia; and the Neurosciences Department (J.M.M., J.S., S.W.), Gosford Hospital, Northern Sydney Central Coast Health, Gosford, New South Wales, Australia.

^* To whom correspondence should be addressed. E-mail: jmaguire{at}nsccahs.health.nsw.gov.au.

Background and Purpose—Platelets and components of the coagulation cascade are known to be instrumental in the pathogenesis of arterial occlusive disorders. The aim of this meta-analysis is to test the hypothesis that genetic variation in the platelet glycoprotein 1b and Factor VII genes influence the occurrence of ischemic stroke. All genetic association studies that examined the R353Q (rs6046) polymorphism of the Factor VII gene and 2 polymorphisms of the platelet glycoprotein (1b) gene (Thr/Met rs6065 and Kozak sequence -5 C/T rs2243093) in relation to ischemic stroke were examined.

Methods—Electronic databases Embase, Medline, and HuGEnet were searched for all years up until June 2006 for all studies that evaluated any of these candidate genes and stroke.

Results—Pooled ORs were calculated with 95% CIs using both fixed and random effects models. Meta-analysis for Factor VII (R353Q) did not detect any effect on ischemic stroke risk. Further estimation resulted in pooled OR₁ QQ versus RR=0.9 (95% CI: 0.4 to 1.9) and pooled OR₂ for RQ versus RR=0.9 (95% CI: 0.6 to 1.4). These results were robust and homogeneous. Pooling ORs for the platelet glycoprotein 1b Kozak variant -5 T/C polymorphism showed extreme heterogeneity with differing effect directions across studies. Fisher's method of pooling was therefore used to calculate a combined probability value, which was highly significant (P<0.001). The pooled OR for platelet glycoprotein 1b Met/Met v Thr/Thr was 1.0 to 2.0, depending on the sensitivity analyses, and for Thr/Met versus Thr/Thr, the pooled OR was between 1.3 and 1.4. These results were consistent, reasonably robust, and implied a dominant genetic effect.

Conclusion—This analysis provides strong evidence that the Factor VII R353Q gene polymorphism is not associated with ischemic stroke, that the Thr/Met polymorphism of GP1b is associated with ischemic stroke in a dominant genetic model, and that the Kozak sequence polymorphism of GP1b may be close to another causative locus that is associated with ischemic stroke.

Key words: Factor VII • meta-analysis • platelet glycoprotein • polymorphism • stroke

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