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Variability in the CIITA gene interacts with HLA in multiple sclerosis

Genes & Immunity volume 15, pages 162–167 (2014)Cite this article

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Abstract

The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04–1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07–1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA–DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.

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References

  1. Compston A, Coles A . Multiple sclerosis. Lancet 2008; 372: 1502–1517.

    Article  CAS  Google Scholar 

  2. Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA, Tiislar M et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 2005; 37: 1108–1112.

    Article  CAS  Google Scholar 

  3. Sawcer S . The complex genetics of multiple sclerosis: pitfalls and prospects. Brain 2008; 131 (Pt 12): 3118–3131.

    Article  Google Scholar 

  4. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219.

    Article  CAS  Google Scholar 

  5. Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O . Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000; 55: 140–148.

    Article  CAS  Google Scholar 

  6. Ascherio A, Munger KL, Lunemann JD . The initiation and prevention of multiple sclerosis. Nat Rev Neurol 2012; 8: 602–612.

    Article  CAS  Google Scholar 

  7. DeSandro A, Nagarajan UM, Boss JM . The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes. Am J Hum Genet 1999; 65: 279–286.

    Article  CAS  Google Scholar 

  8. LeibundGut-Landmann S, Waldburger JM, Krawczyk M, Otten LA, Suter T, Fontana A et al. Mini-review: specificity and expression of CIITA, the master regulator of MHC class II genes. Eur J Immunol 2004; 34: 1513–1525.

    Article  CAS  Google Scholar 

  9. Martin BK, Chin KC, Olsen JC, Skinner CA, Dey A, Ozato K et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 1997; 6: 591–600.

    Article  CAS  Google Scholar 

  10. LeibundGut-Landmann S, Waldburger JM, Reis e Sousa C, Acha-Orbea H, Reith W . MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells. Nat Immunol 2004; 5: 899–908.

    Article  CAS  Google Scholar 

  11. Swanberg M, Lidman O, Padyukov L, Eriksson P, Akesson E, Jagodic M et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet 2005; 37: 486–494.

    Article  CAS  Google Scholar 

  12. Eike MC, Skinningsrud B, Ronninger M, Stormyr A, Kvien TK, Joner G et al. CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations. Genes Immun 2012; 13: 431–436.

    Article  CAS  Google Scholar 

  13. Gyllenberg A, Asad S, Piehl F, Swanberg M, Padyukov L, Van Yserloo B et al. Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes. Genes Immun 2012; 13: 632–640.

    Article  CAS  Google Scholar 

  14. Skinningsrud B, Husebye ES, Pearce SH, McDonald DO, Brandal K, Wolff AB et al. Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. J Clin Endocrinol Metab 2008; 93: 3310–3317.

    Article  CAS  Google Scholar 

  15. Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 2011; 43: 1193–1201.

    Article  CAS  Google Scholar 

  16. Harrison P, Pointon JJ, Farrar C, Harin A, Wordsworth BP . MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients. Rheumatology (Oxford) 2007; 46: 409–411.

    Article  CAS  Google Scholar 

  17. Akkad DA, Jagiello P, Szyld P, Goedde R, Wieczorek S, Gross WL et al. Promoter polymorphism rs3087456 in the MHC class II transactivator gene is not associated with susceptibility for selected autoimmune diseases in German patient groups. Int J Immunogenet 2006; 33: 59–61.

    Article  CAS  Google Scholar 

  18. Bronson PG, Ramsay PP, Seldin MF, Gregersen PK, Criswell LA, Barcellos LF . CIITA is not associated with risk of developing rheumatoid arthritis. Genes Immun 2011; 12: 235–238.

    Article  CAS  Google Scholar 

  19. Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis. Hum Mol Genet 2010; 19: 2331–2340.

    Article  CAS  Google Scholar 

  20. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  CAS  Google Scholar 

  21. International Multiple Sclerosis Genetics Consortium (IMSGC). Refining genetic associations in multiple sclerosis. Lancet Neurol 2008; 7: 567–569.

    Article  Google Scholar 

  22. Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 2011; 70: 897–912.

    Article  CAS  Google Scholar 

  23. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353–1360.

    Article  CAS  Google Scholar 

  24. Gobin SJ, Peijnenburg A, Keijsers V, van den Elsen PJ . Site alpha is crucial for two routes of IFN gamma-induced MHC class I transactivation: the ISRE-mediated route and a novel pathway involving CIITA. Immunity 1997; 6: 601–611.

    Article  CAS  Google Scholar 

  25. Zuvich RL, Bush WS, McCauley JL, Beecham AH, De Jager PL, Ivinson AJ et al. Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Hum Mol Genet 2011; 20: 3517–3524.

    Article  CAS  Google Scholar 

  26. Friese MA, Jones EY, Fugger L . MHC II molecules in inflammatory diseases: interplay of qualities and quantities. Trends Immunol 2005; 26: 559–561.

    Article  CAS  Google Scholar 

  27. Sundqvist E, Sundstrom P, Linden M, Hedstrom AK, Aloisi F, Hillert J et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun 2012; 13: 14–20.

    Article  CAS  Google Scholar 

  28. Sundstrom P, Nystrom M, Ruuth K, Lundgren E . Antibodies to specific EBNA-1 domains and HLA DRB1*1501 interact as risk factors for multiple sclerosis. J Neuroimmunol 2009; 215: 102–107.

    Article  Google Scholar 

  29. Waubant E, Mowry EM, Krupp L, Chitnis T, Yeh EA, Kuntz N et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76: 1989–1995.

    Article  CAS  Google Scholar 

  30. Sundqvist E, Bergstrom T, Daialhosein H, Nystrom M, Sundstrom P, Hillert J et al. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult Scler (e-pub ahead of print 2 September 2013; doi: 10.1177/1352458513494489).

    Article  Google Scholar 

  31. 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 

  32. 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 

  33. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L . Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009; 73: 696–701.

    Article  Google Scholar 

  34. Piehl F, Holmen C, Hillert J, Olsson T . Swedish natalizumab (Tysabri) multiple sclerosis surveillance study. Neurol Sci 2011; 31 (Suppl 3): 289–293.

    Article  Google Scholar 

  35. Roos IM, Kockum I, Hillert J . The interleukin 23 receptor gene in multiple sclerosis: a case-control study. J Neuroimmunol 2008; 194: 173–180.

    Article  CAS  Google Scholar 

  36. Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003; 62: 835–841.

    Article  CAS  Google Scholar 

  37. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis–a genomewide study. N Engl J Med 2007; 357: 1199–1209.

    Article  CAS  Google Scholar 

  38. Landin-Olsson M, Karlsson FA, Lernmark A, Sundkvist G, the Diabetes Incidence Study in Sweden group.. Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the Diabetes Incidence Study in Sweden. Diabetes 1992; 41: 1022–1027.

    Article  CAS  Google Scholar 

  39. Jensen RA, Gilliam LK, Torn C, Landin-Olsson M, Karlsson FA, Palmer JP et al. Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects. J Diabetes Complications 2007; 21: 205–213.

    Article  Google Scholar 

  40. Dahlquist G, Blom L, Tuvemo T, Nystrom L, Sandstrom A, Wall S . The Swedish childhood diabetes study—results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia 1989; 32: 2–6.

    Article  CAS  Google Scholar 

  41. Lindholm E, Agardh E, Tuomi T, Groop L, Agardh CD . Classifying diabetes according to the new WHO clinical stages. Eur J Epidemiol 2001; 17: 983–989.

    Article  CAS  Google Scholar 

  42. Eriksson P, Deguchi H, Samnegard A, Lundman P, Boquist S, Tornvall P et al. Human evidence that the cystatin C gene is implicated in focal progression of coronary artery disease. Arterioscler Thromb Vasc Biol 2004; 24: 551–557.

    Article  CAS  Google Scholar 

  43. Ekelund E, Saaf A, Tengvall-Linder M, Melen E, Link J, Barker J et al. Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis. Am J Hum Genet 2006; 78: 1060–1065.

    Article  CAS  Google Scholar 

  44. Prince JA, Feuk L, Howell WM, Jobs M, Emahazion T, Blennow K et al. Robust and accurate single nucleotide polymorphism genotyping by dynamic allele-specific hybridization (DASH): design criteria and assay validation. Genome Res 2001; 11: 152–162.

    Article  CAS  Google Scholar 

  45. Roach JC, Deutsch K, Li S, Siegel AF, Bekris LM, Einhaus DC et al. Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in sweden. Am J Hum Genet 2006; 79: 614–627.

    Article  CAS  Google Scholar 

  46. Olerup O, Zetterquist H . HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39: 225–235.

    Article  CAS  Google Scholar 

  47. Graham J, Hagopian WA, Kockum I, Li LS, Sanjeevi CB, Lowe RM et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002; 51: 1346–1355.

    Article  CAS  Google Scholar 

  48. Dilthey A, Leslie S, Moutsianas L, Shen J, Cox C, Nelson MR et al. Multi-population classical HLA type imputation. PLoS Comput Biol 2013; 9: e1002877.

    Article  CAS  Google Scholar 

  49. Cortes A, Brown MA . Promise and pitfalls of the Immunochip. Arthritis Res Ther 2011; 13: 101.

    Article  Google Scholar 

  50. Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A . Calculating measures of biological interaction. Eur J Epidemiol 2005; 20: 575–579.

    Article  Google Scholar 

  51. R Development Core Team 2011 R: A Language and Environment for Statistical Computing In R Foundation for Statistical Computing: Vienna, Austria.

  52. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Juvenile Diabetes Research Foundation International (2-2000-570 and 1-2001-873), the Swedish Research Council, Swedish Diabetes Foundation, Swedish Child Diabetes Foundation, The Swedish association of persons with neurological disabilities (Neurologiskt Handikappades Riksförbund, NHR), Novo Nordisk Foundation, Magnus Bergvalls Foundation, Neuropromise (LSHM-CT-2005-018637) and the International Multiple Sclerosis Genetics Consortium (IMSGC). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. M Aili, L E Bååth, E Carlsson, H Edenwall, G Forsander, B W Granström, I Gustavsson, R Hanas, L Hellenberg, H Hellgren, E Holmberg, H Hörnell, Sten-A Ivarsson, C Johansson, G Jonsell, K Kockum, B Lindblad, A Lindh, J Ludvigsson, U Myrdal, J Neiderud, K Segnestam, S Sjö, L Skogsberg, L Strömberg, U Ståhle, B Thalme, K Tullus, T Tuvemo, M Wallensteen, O Westphal and J Åman: Members of the Swedish Childhood Diabetes Study Group are listed at the end of the article.

  2. H Arnqvist, E Björck, J Eriksson, L Nyström, L O Ohlson, B Scherstén and J Östman: Members of the Diabetes Incidence in Sweden Study Group are listed at the end of the article.

Authors and Affiliations

  1. Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden

    A Gyllenberg, F Piehl, I L Bomfim, T Olsson & I Kockum

  2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    L Alfredsson

  3. Department of Clinical Neuroscience, Multiple Sclerosis Research Group, Karolinska Institutet, Stockholm, Sweden

    J Hillert

  4. Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden

    L Padyukov

  5. Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University Hospital, Lund, Sweden

    M Orho-Melander & E Lindholm

  6. Department of Endocrinology, Skane University Hospital Lund, Lund University, Lund, Sweden

    M Landin-Olsson

  7. Department of Medicine, Lund University Hospital, Lund, Sweden

    Å Lernmark

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  1. A Gyllenberg
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  2. F Piehl
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Consortia

The Swedish Childhood Diabetes Study Group

  • M Aili
  • , L E Bååth
  • , E Carlsson
  • , H Edenwall
  • , G Forsander
  • , B W Granström
  • , I Gustavsson
  • , R Hanas
  • , L Hellenberg
  • , H Hellgren
  • , E Holmberg
  • , H Hörnell
  • , Sten-A Ivarsson
  • , C Johansson
  • , G Jonsell
  • , K Kockum
  • , B Lindblad
  • , A Lindh
  • , J Ludvigsson
  • , U Myrdal
  • , J Neiderud
  • , K Segnestam
  • , S Sjö
  • , L Skogsberg
  • , L Strömberg
  • , U Ståhle
  • , B Thalme
  • , K Tullus
  • , T Tuvemo
  • , M Wallensteen
  • , O Westphal
  •  & J Åman

The Diabetes Incidence in Sweden Study Group

  • H Arnqvist
  • , E Björck
  • , J Eriksson
  • , L Nyström
  • , L O Ohlson
  • , B Scherstén
  •  & J Östman

Corresponding author

Correspondence to A Gyllenberg.

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The authors declare no conflict of interest.

Additional information

All from Departments of Paediatrics in Sweden: M Aili, Halmstad; LE Bååth, Östersund; E Carlsson, Kalmar; H Edenwall, Karlskrona; G Forsander, Falun; BW Granström, Gällivare; I Gustavsson, Skellefteå; R Hanås, Uddevalla; L Hellenberg, Nyköping; H Hellgren, Lidköping; E Holmberg, Umeå; H Hörnell, Hudiksvall; Sten-A Ivarsson, Malmö; C Johansson, Jönköping; G Jonsell, Karlstad; K Kockum, Ystad, B Lindblad, Mölndal; A Lindh, Borås; J Ludvigsson, Linköping; U Myrdal, Vä sterås; J Neiderud, Helsingborg; K Segnestam, Eskilstuna; S Sjö blad, Lund; L Skogsberg, Boden; L Strömberg, Norrköping; U Ståhle, Ängelholm; B Thalme, Huddinge; K Tullus, Danderyd; T Tuvemo, Uppsala; M Wallensteen, Stockholm; O Westphal, Göteborg; and J Åman, Örebro.

H Arnqvist, Department of Internal Medicine, University of Linköping, Linköping; E Björck, Department of Medicine, University Hospital, Uppsala; J Eriksson, Department of Medicine, University of Umeå, Umeå; L Nyström, Department of Epidemiology and Public Health, University of Umeå, Umeå; LO Ohlson, Sahlgrenska Hospital, University of Göteborg, Göteborg; B Scherstén, Department of Community Health Sciences, Dahlby, University of Lund, Lund; J Östman, Center for Metabolism and Endocrinology, Huddinge University Hospital, Stockholm.

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Gyllenberg, A., Piehl, F., Alfredsson, L. et al. Variability in the CIITA gene interacts with HLA in multiple sclerosis. Genes Immun 15, 162–167 (2014). https://doi.org/10.1038/gene.2013.71

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