Base Pairing; Carrier Proteins/genetics/metabolism; Case-Control Studies; Crohn Disease/genetics; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide/genetics; Reproducibility of Results
Abstract :
[en] 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 (P(combined) = 3.49 x 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-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Villani, Alexandra-Chloé
Lemire, Mathieu
Fortin, Geneviève
Louis, Edouard ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie - Relations académiques et scientifiques (Médecine)
Silverberg, Mark S.
Collette, Catherine
Baba, Nobuyasu
Libioulle, Cécile ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Belaiche, Jacques ; Centre Hospitalier Universitaire de Liège - CHU > Gastro-Entérologie-Hépatologie
Agostini, L. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319-325 (2004).
Mariathasan, S. & Monack, D.M. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat. Rev. Immunol. 7, 31-40 (2007).
Podolsky, D.K. Inflammatory bowel disease. N. Engl. J. Med. 347, 417-429 (2002).
Pétrilli, V., Dostert, C., Muruve, D.A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615-622 (2007).
Martinon, F. & Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14, 10-22 (2007).
Taylor, J. et al. ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. Genome Res. 16, 1596-1604 (2006).
de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217-1223 (2005).
Kummer, J.A. et al. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J. Histochem. Cytochem. 55, 443-452 (2007).
Martinon, F., Agostini, L., Meylan, E. & Tschopp, J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr. Biol. 14, 1929-1934 (2004).
Hawkins, P.N., Lachmann, H.J. & McDermott, M.F. Interleukin-1- receptor antagonist in the Muckle-Wells syndrome. N. Engl. J. Med. 348, 2583-2584 (2003).
Hoffman, H.M. et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364, 1779-1785 (2004).
Li, J. et al. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum. Mol. Genet. 13, 1715-1725 (2004).
Van Heel, D.A. et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365, 1794-1796 (2005).
Kramer, M., Netea, M.G., de Jong, D.J., Kullberg, B.J. & Adema, G.J. Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation. J. Leukoc. Biol. 79, 860-866 (2006).
van Beelen, A.J. et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660-669 (2007).
Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461-1463 (2006).
Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596-604 (2007).
Libioulle, C. et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).
Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830-832 (2007).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955-962 (2008).
Lennard-Jones, J.E. Classification of inflammatory bowel disease. Scand. J. Gastroenterol. Suppl. 170, 2-6 (1989).
Silverberg, M.S. et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can. J. Gastroenterol. (Suppl A), 19, 5-36 (2005).
Bell, P.A. et al. SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques Suppl 70-72, 74, 76-77 (2002).
van den Boom, D. & Ehrich, M. Discovery and identification of sequence polymorphisms and mutations with MALDI-TOF MS. Methods Mol. Biol. 366, 287-306 (2007).
Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263-265 (2005).
Dudbridge, F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum. Hered. 66, 87-98 (2008).
Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506-516 (1993).
Holland, P.M., Abramson, R.D., Watson, R. & Gelfand, D.H. Detection of specific polymerase chain reaction product by utilizing the 5′→3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc. Natl. Acad. Sci. USA 88, 7276-7280 (1991).