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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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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Affiliations

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

    • Alexandra-Chloé Villani
    • , Geneviève Fortin
    • , Catherine Collette
    •  & Denis Franchimont
  2. McGill University and Génome Québec Innovation Centre, 740 Doctor Penfield Avenue, Montréal, Québec H3A 1A4, Canada.

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

    • Mathieu Lemire
    •  & Thomas J Hudson
  4. Division of Gastroenterology, CHU, Université de Liège, 13 avenue de l'Hôpital Bât. B35, 4000 Liège, Belgium.

    • Edouard Louis
    • , Cécile Libioulle
    •  & Jacques Belaiche
  5. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

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

    • Nobuyasu Baba
    •  & Marika Sarfati
  7. Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec H3A 1A1, 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, Québec G7H 2B1, Canada.

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

    • Albert Cohen
  10. Centre Hospitalier Universitaire de Sherbrooke–Hôtel-Dieu, 580 rue Bowen Sud, Sherbrooke, Québec J1G 2E8, 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, 3000 Leuven, Belgium.

    • Paul Rutgeerts
    •  & Severine Vermeire
  13. Université de Montréal and Montréal Heart Institute, Research Center, 5000 rue Bélanger, Montréal, Québec H1T 1C8, Canada.

    • John D Rioux
  14. Department of Gastroenterology, Erasme Hospital, ULB, 808 Lennik road, 1070 Brussels, Belgium.

    • 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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DOI

https://doi.org/10.1038/ng.285

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