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A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes

Genes & Immunity volume 10, pages 120–124 (2009)Cite this article

Abstract

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06–1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04–1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.

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References

  1. Tschopp J, Martinon F, Burns K . NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003; 4: 95–104.

    Article  CAS  Google Scholar 

  2. Martinon F, Tschopp J . NLRs join TLRs as innate sensors of pathogens. Trends Immunol 2005; 26: 447–454.

    Article  CAS  Google Scholar 

  3. Martinon F, Hofmann K, Tschopp J . The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol 2001; 11: R118–R120.

    Article  CAS  Google Scholar 

  4. Ting JP, Davis BK . CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 2005; 23: 387–414.

    Article  CAS  Google Scholar 

  5. Macaluso F, Nothnagel M, Parwez Q, Petrasch-Parwez E, Bechara FG, Epplen JT et al. Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 2007; 16: 692–698.

    Article  CAS  Google Scholar 

  6. Martinon F, Gaide O, Petrilli V, Mayor A, Tschopp J . NALP inflammasomes: a central role in innate immunity. Semin Immunopathol 2007; 29: 213–229.

    Article  CAS  Google Scholar 

  7. Martinon F, Tschopp J . Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004; 117: 561–574.

    Article  CAS  Google Scholar 

  8. Martinon F, Burns K, Tschopp J . The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417–426.

    Article  CAS  Google Scholar 

  9. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007; 356: 1216–1225.

    Article  CAS  Google Scholar 

  10. Jin Y, Birlea SA, Fain PR, Spritz RA . Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol 2007; 127: 2558–2562.

    Article  CAS  Google Scholar 

  11. Undlien DE, Lie BA, Thorsby E . HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 2001; 17: 93–100.

    Article  CAS  Google Scholar 

  12. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  Google Scholar 

  13. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857–864.

    Article  CAS  Google Scholar 

  14. Ting JP, Kastner DL, Hoffman HM . CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 2006; 6: 183–195.

    Article  CAS  Google Scholar 

  15. Skinningsrud B, Husebye ES, Pearce SH, McDonald DO, Brandal K, Boe Wolff A 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 

  16. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.

    Article  CAS  Google Scholar 

  17. Church LD, Cook GP, McDermott MF . Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008; 4: 34–42.

    Article  CAS  Google Scholar 

  18. Helqvist S, Zumsteg UW, Spinas GA, Palmer JP, Mandrup-Poulsen T, Egeberg J et al. Repetitive exposure of pancreatic islets to interleukin-1 beta. An in vitro model of pre-diabetes? Autoimmunity 1991; 10: 311–318.

    Article  CAS  Google Scholar 

  19. Bjornvold M, Undlien DE, Joner G, Dahl-Jorgensen K, Njolstad PR, Akselsen HE et al. Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes. Diabetologia 2008; 51: 589–596.

    Article  CAS  Google Scholar 

  20. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000; 355: 873–876.

    Article  Google Scholar 

  21. 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 

  22. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

    Article  CAS  Google Scholar 

  23. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

    Article  CAS  Google Scholar 

  24. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390–392.

    Google Scholar 

  25. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  26. 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 

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Acknowledgements

We are indebted to each patient and the Norwegian Bone Marrow Registry for contributing with DNA samples for healthy controls, and The Norwegian Study Group for Childhood Diabetes for collection of type 1 diabetes samples. Vibeke Lilleby and Inge M Gilboe are thanked for collecting the lupus samples. Berit Flatø and Anne Marit Selvaag, Rikshospitalet-Radiumhospitalet Medical Centre, are acknowledged for collecting the juvenile idiopathic arthritis samples. Furthermore, we thank Siri Flåm, Rikshospitalet, Sigrid Erdal, Haukeland University Hospital, and Alice Stormyr and Hanne Akselsen, Ullevål University Hospital, for help with genotyping. The study was supported by grants from The Seventh Framework Programme ‘Euradrenal,’ The Western and South-Eastern Regional Health Authorities, the Norwegian Research Council and the University of Bergen.

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Author notes

  1. P M Knappskog and E S Husebye: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    N F Magitta, A S Bøe Wolff, S Johansson & P M Knappskog

  2. Institute of Clinical Medicine, University of Bergen, Bergen, Norway

    N F Magitta, S Johansson, K-M Myhr, P R Njølstad & P M Knappskog

  3. Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    N F Magitta

  4. Department of Medicine, Haukeland University Hospital, Bergen, Norway

    A S Bøe Wolff & E S Husebye

  5. Institute of Medicine, University of Bergen, Bergen, Norway

    A S Bøe Wolff & E S Husebye

  6. Institute of Biomedicine, University of Bergen, Bergen, Norway

    S Johansson

  7. Institute of Medical Genetics, University of Oslo, Oslo, Norway

    B Skinningsrud & D E Undlien

  8. Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway

    B Skinningsrud & D E Undlien

  9. Institute of Immunology, Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway

    B A Lie

  10. Department of Neurology, Haukeland University Hospital, Bergen, Norway

    K-M Myhr

  11. Department of Paediatrics, Ullevål University Hospital, Oslo, Norway

    G Joner

  12. Institute of Health Management and Health Economics, University of Oslo, Oslo, Norway

    G Joner

  13. Department of Paediatrics, Haukeland University Hospital, Bergen, Norway

    P R Njølstad

  14. Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway

    T K Kvien

  15. Department of Rheumatology, Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway

    Ø Førre

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  1. N F Magitta
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  8. G Joner
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Corresponding author

Correspondence to E S Husebye.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Magitta, N., Bøe Wolff, A., Johansson, S. et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun 10, 120–124 (2009). https://doi.org/10.1038/gene.2008.85

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  • DOI: https://doi.org/10.1038/gene.2008.85

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