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Common variants in the NLRP3 region contribute to Crohn's disease susceptibility

Nature Genetics volume 41, pages 71–76 (2009)Cite this article

Abstract

We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (Pcombined = 3.49 × 10−9, odds ratio = 1.78, confidence interval = 1.47–2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1β production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders1,2. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.

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Figure 1: Association results for the five Crohn's disease sample sets.
Figure 2: NLRP3 functional study results.

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Acknowledgements

We thank the study participants and their families for their collaboration; A. Montpetit and the genotyping and sequencing platforms of the McGill University and Genome Québec Innovation Centre for their technical assistance; T. McKenzie, G. Bonventi and C. Landolt-Maticorena for their help with acquisition and preparation of the PBCs; F. Martinon and J. Tschopp for their technical assistance in designing the functional studies; and T. Kwan for helpful discussion. This research was supported by grants to D.F. from the Canada Foundation for Innovation, the Canada Research Chair program, the Research Institute of the McGill University Health Centre and the Crohn's & Colitis Foundation of Canada (CCFC). A.-C.V. is supported by a PhD training award from the Fonds de la recherche en santé du Québec. M.S.S. is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK624230), the CCFC and the Mount Sinai Hospital Gale and Graham Wright Research Chair in Digestive Diseases. J.D.R. is funded by grants from the National Institutes of Allergy and Infectious Diseases (AI065687 and AI067152), the National Institute of Diabetes and Digestive and Kidney Diseases (DK064869 and DK062432) and the Crohn's and Colitis Foundation of America (SRA512). E.L. is a senior research associate at the Belgium Foundation for Scientific Research (FNRS). S.V. is a clinical investigator for the Funds for Scientific Research of Flanders. T.J.H. is the recipient of an Investigator Award from the Ontario Institute for Cancer Research through funding from the Government of Ontario's Ministry of Research and Innovation. D.F. is a senior clinical scientist at the Belgium FNRS. None of the funding agencies had any role in the design and conduct of the study; in the collection, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript.

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Authors and Affiliations

  1. Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montréal, H3G 1A4, Québec, Canada

    Alexandra-Chloé Villani, Geneviève Fortin, Catherine Collette & Denis Franchimont

  2. McGill University and Génome Québec Innovation Centre, 740 Doctor Penfield Avenue, Montréal, H3A 1A4, Québec, Canada

    Alexandra-Chloé Villani

  3. Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, M5G 0A3, Ontario, Canada

    Mathieu Lemire & Thomas J Hudson

  4. Division of Gastroenterology, CHU, Université de Liège, 13 avenue de l'Hôpital Bât. B35, Liège, 4000, Belgium

    Edouard Louis, Cécile Libioulle & Jacques Belaiche

  5. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Mark S Silverberg

  6. Immunoregulation Laboratory, CHUM Research Center, Université de Montréal, 1560 rue Sherbrooke Est, Montréal, H2L 4M1, Québec, Canada

    Nobuyasu Baba & Marika Sarfati

  7. Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, H3A 1A1, Québec, Canada

    Alain Bitton

  8. Université de Montréal, Centre de médecine génique communautaire de l'Université de Montréal, Hôpital universitaire de Chicoutimi, 555 boulevard de l'Université, Chicoutimi, G7H 2B1, Québec, Canada

    Daniel Gaudet

  9. Jewish General Hospital, 3755 chemin de la Côte-Sainte-Catherine, Montréal, H3T 1E2, Québec, Canada

    Albert Cohen

  10. Centre Hospitalier Universitaire de Sherbrooke–Hôtel-Dieu, 580 rue Bowen Sud, Sherbrooke, J1G 2E8, Québec, Canada

    Diane Langelier

  11. Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, 399 Bathurst Street, University of Toronto, Toronto, Ontario M5T 2S8, Canada.,

    Paul R Fortin & Joan E Wither

  12. Department of Gastroenterology, University Hospital Gasthuisberg, 49 Herestraat, Leuven, 3000, Belgium

    Paul Rutgeerts & Severine Vermeire

  13. Université de Montréal and Montréal Heart Institute, Research Center, 5000 rue Bélanger, Montréal, H1T 1C8, Québec, Canada

    John D Rioux

  14. Department of Gastroenterology, Erasme Hospital, ULB, 808 Lennik road, Brussels, 1070, Belgium

    Denis Franchimont

Authors
  1. Alexandra-Chloé Villani
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  2. Mathieu Lemire
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  5. Mark S Silverberg
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  17. Paul Rutgeerts
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  18. John D Rioux
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  19. Severine Vermeire
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  20. Thomas J Hudson
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  21. Denis Franchimont
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Contributions

A.-C.V., G.F. and D.F. conceived and designed the experiments. A.-C.V., G.F., C.C. and N.B. did the experiments. A.-C.V. and M.L. analyzed the data. E.L., M.S.S., C.L., J.B., A.B., D.G., A.C., D.L., P.R.F., J.E.W., M.S., P.R., J.D.R., S.V., T.J.H. and D.F. provided study samples. A.-C.V., M.L. and D.F. wrote the paper, with contributions from all authors.

Corresponding authors

Correspondence to Alexandra-Chloé Villani or Denis Franchimont.

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Supplementary Methods, Supplementary Tables 1–6 and Supplementary Figures 1 and 2 (PDF 3222 kb)

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Villani, AC., Lemire, M., Fortin, G. et al. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet 41, 71–76 (2009). https://doi.org/10.1038/ng.285

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