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From the School of Public Health (R.M.B., P.P.R., L.F.B.), Division of Epidemiology, University of California, Berkeley; Center for Human Genetics Research (J.L.H.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (S.L.H., J.R.O., L.F.B.), University of California, San Francisco; Center for Human Genetics (M.A.P.-V., S. Schmidt), Duke University Medical Center, Durham, NC; University of Cambridge (A.C., S. Sawcer), Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, UK; Institute of Neurological Sciences (R.C., A.Q.), National Research Council, Mangone, Cosenza, Italy; Department of Neurology, Ophthalmology, Otolaryngology and Psychiatry (G.S.), University of Palermo, Italy; Institute of Neurology (A.Q.), University Magna Graecia, Catanzaro, Italy; VU University Medical Center (C.H.P., B.M.J.U., J.N.P.Z.), Department of Neurology, Amsterdam, The Netherlands; Keele Multiple Sclerosis Research Group (C.P.H.), North Staffordshire University Hospital, Stoke-On-Trent, UK; Centre For Integrated Genomic Medical Research (CIGMR) (W.E.R.O.), University Medical School, Manchester, UK; Neurology Department (S.W.), Derriford Hospital, Plymouth, UK; Department of Neurology (C.E., F.F., R.S.), Institute for Medical Molecular Biology and Biochemistry (H.S.), and Section Neuroradiology, Department of Radiology (F.F.), Medical University Graz, Austria; Division of Neurology (J.H., T.M.), Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden; Memory Disorders Research Unit 6702 (P.H.), Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark; Department of Neurology (M.N., S.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; Health and Life Sciences Research Institute (P.M., M.S.), School of Health Sciences, University of Minho, Braga, Portugal; Neurology (M.E.R.), Hospital S. João, Porto, Portugal; Department of Neurology (H.K., B.Z.-P.), The Medical University of Warsaw, Poland; Queen’s Medical Centre (N.E.), Department of Neurology, Nottingham, UK; Radcliffe Infirmary (J.P.), Oxford University, UK; and Kaiser Permanente Division of Research (L.F.B.), Oakland, CA.
Address correspondence and reprint requests to Dr Barcellos, 140 Warren Hall MC #7360, School of Public Health, Division of Epidemiology, University of California, Berkeley, CA 94720; e-mail: barcello{at}genepi.berkeley.edu
Background: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism.
Methods: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity.
Results: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of 
2 or 4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96–1.34 and OR 0.89, 95% CI 0.78–1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration.
Conclusion: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
Supported by National Multiple Sclerosis Society grant RG2901 (to J.R.O.); NIH grants NS026799 and NS049477 (to J.R.O. and S.L.H.) and NS049510 (to L.F.B.); and the Nancy Davis Foundation (to S.L.H. and L.F.B.).
Disclosure: The authors report no conflicts of interest.
Received October 7, 2005. Accepted in final form January 19, 2006.
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Neurology 2006 66: 1292-1293.
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