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Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis

Abstract

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor α chain (IL7Rα), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Rα and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.

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Figure 1: Expression analysis of IL7R and IL7 in individuals with multiple sclerosis.

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References

  1. Noguchi, M. et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science 262, 1877–1880 (1993).

    Article  CAS  Google Scholar 

  2. Ye, S.K. et al. Induction of germline transcription in the TCRgamma locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity 11, 213–223 (1999).

    Article  CAS  Google Scholar 

  3. Ebers, G.C. et al. A full genome search in multiple sclerosis. Nat. Genet. 13, 472–476 (1996).

    Article  CAS  Google Scholar 

  4. Zhang, Z. et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 6, 145–152 (2005).

    Article  CAS  Google Scholar 

  5. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  6. Gregory, S.G. et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. advance online publication 29 July 2007 (doi:10.1038/ng2103).

    Article  CAS  Google Scholar 

  7. de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    Article  CAS  Google Scholar 

  8. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  Google Scholar 

  9. Svejgaard, A. & Ryder, L.P. HLA and disease association: detecting the strongest association. Tissue Antigens 43, 18–27 (1994).

    Article  CAS  Google Scholar 

  10. Sawcer, S. et al. A high-density screen for linkage in multiple sclerosis. Am. J. Hum. Genet. 77, 454–467 (2005).

    Article  Google Scholar 

  11. Burwick, R.M. et al. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers. Neurology 66, 1373–1383 (2006).

    Article  CAS  Google Scholar 

  12. Roxburgh, R.H. et al. No evidence of a significant role for CTLA-4 in multiple sclerosis. J. Neuroimmunol. 171, 193–197 (2006).

    Article  CAS  Google Scholar 

  13. Teutsch, S.M., Booth, D.R., Bennetts, B.H., Heard, R.N. & Stewart, G.J. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur. J. Hum. Genet. 11, 509–515 (2003).

    Article  CAS  Google Scholar 

  14. Booth, D.R. et al. Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis. J. Mol. Med. 83, 822–830 (2005).

    Article  CAS  Google Scholar 

  15. Kurz, T. et al. Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci. J. Allergy Clin. Immunol. 118, 396–402 (2006).

    Article  CAS  Google Scholar 

  16. Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617–619 (2006).

    Article  CAS  Google Scholar 

  17. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  Google Scholar 

  18. Hugot, J.P. et al. Association of NOD2 leucine-rich repeat variant with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  CAS  Google Scholar 

  19. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  CAS  Google Scholar 

  20. Hampe, J. et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357, 1925–1928 (2001).

    Article  CAS  Google Scholar 

  21. Sigurdsson, S. et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528–537 (2005).

    Article  CAS  Google Scholar 

  22. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    Article  CAS  Google Scholar 

  23. Begovich, A.B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the patients and volunteers who participated in this study. This study was supported by grants from the Swedish Research Council (project number 11220), the Norwegian Research Council (project numbers 1154888/40 and 148351/300), the Eastern Norwegian Regional Health Authority (project number 29300604), the Danish Multiple Sclerosis Society, the Warwara Larsen Foundation, NeuroproMiSe LSMH-CT-2005-018637, the Swedish Society of the Neurologically Disabled, the Bibbi and Nils Jensens Foundation and the Swedish Foundation for Strategic Research and Karolinska Institutet. We are grateful to the Knut and Alice Wallenberg Foundation.

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Contributions

F.L., K.D., H.S. and J.H. planned, designed and managed the study. K.D. performed the genotyping; F.L. and I.K. performed the statistical analysis. J.H. and T.O. collected the Swedish patient and control groups. E.I., E.W., M.K., and T.O. collected material for and performed the expression analyses of IL7R and IL7. A.O., L.P.R., J.S., H.F.H. and E.G.C. took part in the planning of the study and contributed the non-Swedish groups of affected individuals and controls. J.H. and F.L. wrote the manuscript with assistance from all coauthors.

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Correspondence to Jan Hillert.

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The authors declare no competing financial interests.

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Lundmark, F., Duvefelt, K., Iacobaeus, E. et al. Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39, 1108–1113 (2007). https://doi.org/10.1038/ng2106

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