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Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis

Abstract

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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Figure 1: Physical map and association analysis of SNPs from IL7R in US, European and combined family-based and case-control data sets.
Figure 2: Transfections and splicing analysis of IL7R minigenes.

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Acknowledgements

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.).

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J.R.O., S.L.H., R.L., S.J.S., D.A.S.C. and B.D. collected and reviewed the participant samples and clinical information. J.L.H., M.A.P.-V. and S.G.G. designed the overall study. J.H. performed genotyping and sequencing using assays designed by and under the direction of S.G.G. M.B. and A.G. performed genotyping under the direction of S.J.S., and S.J.C. performed genotyping under the direction of J.R.O. S.J.C. performed expression assays under the direction of J.R.O. M.A.G.-B. and P.S. designed the differential splicing assays that were performed by P.S. M.A.G.-B., S.G.G. and P.S. interpreted the differential splicing assays, and M.A.G.-B. wrote the relevant portions of the manuscript. Statistical analysis and interpretation of the data was performed by S.S., A.P., L.F.B., J.L.M., J.L.H. and M.A.P.-V. Molecular analysis and interpretation was performed by S.G.G., J.R.O. and M.A.G.-B. The manuscript was written by S.G.G., S.S., J.L.H. and M.A.P.-V., with review and contributions by all authors. J.L.H. and M.A.P-V. contributed equally to this work.

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Correspondence to Margaret A Pericak-Vance or Jonathan L Haines.

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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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Gregory, S., Schmidt, S., Seth, P. et al. Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis. Nat Genet 39, 1083–1091 (2007). https://doi.org/10.1038/ng2103

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