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IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

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References

  1. Rosati G . The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001; 22: 117–139.

    Article  CAS  Google Scholar 

  2. Sotgiu S, Pugliatti M, Sotgiu A, Sanna A, Rosati G . Does the ‘hygiene hypothesis’ provide an explanation for the high prevalence of multiple sclerosis in Sardinia? Autoimmunity 2003; 36: 257–260.

    Article  Google Scholar 

  3. Dyment DA, Willer CJ, Scott B, Armstrong H, Ligers A, Hillert J et al. Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 2001; 3: 145–151.

    Article  CAS  Google Scholar 

  4. Sadovnick AD, Ebers GC, Dyment DA, Risch NJ . Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group. Lancet 1996; 347: 1728–1730.

    Article  CAS  Google Scholar 

  5. Lindsey JW . Familial recurrence rates and genetic models of multiple sclerosis. Am J Med Genet A 2005; 135: 53–58.

    Article  Google Scholar 

  6. Oksenberg JR, Barcellos LF . Multiple sclerosis genetics: leaving no stone unturned. Genes Immun 2005; 6: 375–387.

    Article  CAS  Google Scholar 

  7. Haines JL, Terwedow HA, Burgess K, Pericak-Vance MA, Rimmler JB, Martin ER et al. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet 1998; 7: 1229–1234.

    Article  CAS  Google Scholar 

  8. Hillert J . Multiple sclerosis: postlinkage genetics. Clin Neurol Neurosurg 2006; 108: 220–222.

    Article  Google Scholar 

  9. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007; 39: 1108–1113.

    Article  CAS  Google Scholar 

  10. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007; 39: 1083–1091.

    Article  CAS  Google Scholar 

  11. The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  Google Scholar 

  12. Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 2005; 6: 145–152.

    Article  CAS  Google Scholar 

  13. Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C et al. A full genome search in multiple sclerosis. Nat Genet 1996; 13: 472–476.

    Article  CAS  Google Scholar 

  14. Oturai A, Larsen F, Ryder LP, Madsen HO, Hillert J, Fredrikson S et al. Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis. Ann Neurol 1999; 46: 612–616.

    Article  CAS  Google Scholar 

  15. Akesson E, Coraddu F, Marrosu MG, Massacesi L, Hensiek A, Harbo HF et al. Refining the linkage analysis on chromosome 10 in 449 sib-pairs with multiple sclerosis. J Neuroimmunol 2003; 143: 31–38.

    Article  CAS  Google Scholar 

  16. Matesanz F, Caro-Maldonado A, Fedetz M, Fernandez O, Milne RL, Guerrero M et al. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J Neurol 2007; 254: 682–684.

    Article  CAS  Google Scholar 

  17. Sawcer S . A new era in the genetic analysis of multiple sclerosis. Curr Opin Neurol 2006; 19: 237–241.

    Article  Google Scholar 

  18. Ramagopalan SV, Anderson C, Sadovnick AD, Ebers GC . Genomewide study of multiple sclerosis. N Engl J Med 2007; 357: 2199–2200.

    Article  CAS  Google Scholar 

  19. Matesanz F, Fernandez O, Alcina A . Genomewide study of multiple sclerosis. N Engl J Med 2007; 357: 2200–2201.

    CAS  PubMed  Google Scholar 

  20. Bourgain C, Genin E, Cox N, Clerget-Darpoux F . Are genome-wide association studies all that we need to dissect the genetic component of complex human diseases? Eur J Hum Genet 2007; 15: 260–263.

    Article  CAS  Google Scholar 

  21. Clerget-Darpoux F, Elston RC . Are linkage analysis and the collection of family data dead? Prospects for family studies in the age of genome-wide association. Hum Hered 2007; 64: 91–96.

    Article  Google Scholar 

  22. Hafler DA, Slavik JM, Anderson DE, O’Connor KC, De Jager P, Baecher-Allan C . Multiple sclerosis. Immunol Rev 2005; 204: 208–231.

    Article  CAS  Google Scholar 

  23. Seddon B, Tomlinson P, Zamoyska R . Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol 2003; 4: 680–686.

    Article  CAS  Google Scholar 

  24. He YW, Malek TR . Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells. J Exp Med 1996; 184: 289–293.

    Article  CAS  Google Scholar 

  25. McKay FC, Swain LI, Schibeci SD, Rubio JP, Kilpatrick TJ, Heard RN et al. Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun 2008; 9: 1–6.

    Article  CAS  Google Scholar 

  26. Peltonen L . Old suspects found guilty—the first genome profile of multiple sclerosis. N Engl J Med 2007; 357: 927–929.

    Article  CAS  Google Scholar 

  27. Marrosu MG . Susceptibility to multiple sclerosis: the role of interleukin genes. Lancet Neurol 2007; 6: 846–847.

    Article  Google Scholar 

  28. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

    Article  CAS  Google Scholar 

  29. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

    Article  CAS  Google Scholar 

  30. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J et al. The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 1988; 45: 1069–1077.

    Article  CAS  Google Scholar 

  31. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36: 1319–1325.

    Article  CAS  Google Scholar 

  32. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the members of REFGENSEP, a national network for the study of MS genetics in France for their active contribution and for referring patients. REFGENSEP is supported by grants from INSERM, AFM, ARSEP, Groupe Malakoff and Biogen-Idec, and received help from Genethon and CIC Pitié-Salpêtrière. The DNA bank from Würzburg was supported by a grant from the Gemeinnützige Hertie Stiftung (GHS). We gratefully acknowledge expert technical assistance of S Damast, S Sauer and M Koedel.

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Weber, F., Fontaine, B., Cournu-Rebeix, I. et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 9, 259–263 (2008). https://doi.org/10.1038/gene.2008.14

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