Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor α chain ( IL7R ) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 × 10−7). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.
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We thank all affected individuals and families who participated in this study and the collaborating clinics and physicians for referring individuals to the study. We also thank J. van der Walt, K. McDowell and W. Pope for their laboratory and technical assistance and C. DeLoa for clinical data management. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. A.G. is a Postdoctoral Fellow of the Research Foundation - Flanders (FWO - Vlaanderen). B.D. is supported by the Research Council of the University of Leuven. This research was supported by US National Institutes of Health grants NS32830 (J.L.H., M.A.P.-V.), NS26799 (S.L.H., J.R.O.), NS049477 (J.L.H., J.R.O., S.L.H., M.A.P.-V., S.J.S. and D.A.S.C.), GM63090 (M.A.G.-B.) and NMSS RG 2901C6 (J.R.O.) and a postdoctoral grant from the NMSS, FG 1718-A-1 (J.L.M.).
A patent application based on this work has been filed by J.L.H., M.A.P.-V., S.G.G., S.S. and M.A.G.-B.
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