APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.
Burwick RM., Ramsay PP., Haines JL., Hauser SL., Oksenberg JR., Pericak-Vance MA., Schmidt S., Compston A., Sawcer S., Cittadella R., Savettieri G., Quattrone A., Polman CH., Uitdehaag BM., Zwemmer JN., Hawkins CP., Ollier WE., Weatherby S., Enzinger C., Fazekas F., Schmidt H., Schmidt R., Hillert J., Masterman T., Hogh P., Niino M., Kikuchi S., Maciel P., Santos M., Rio ME., Kwiecinski H., Zakrzewska-Pniewska B., Evangelou N., Palace J., Barcellos LF.
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 epsilon2 or epsilon4 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.