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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NCBI Reference Sequence
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.
Supplementary Methods, Supplementary Tables 1–6 and Supplementary Figures 1 and 2
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Frontiers in Immunology (2019)