Genotype-phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients.
Clinical characteristics
Inflammatory bowel disease
NLRP3 inflammasome
Single nucleotide polymorphisms
Journal
BMC gastroenterology
ISSN: 1471-230X
Titre abrégé: BMC Gastroenterol
Pays: England
ID NLM: 100968547
Informations de publication
Date de publication:
03 Aug 2021
03 Aug 2021
Historique:
received:
17
01
2021
accepted:
10
07
2021
entrez:
4
8
2021
pubmed:
5
8
2021
medline:
6
8
2021
Statut:
epublish
Résumé
Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.
Sections du résumé
BACKGROUND
BACKGROUND
Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS).
METHODS
METHODS
We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients.
RESULTS
RESULTS
In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays.
CONCLUSIONS
CONCLUSIONS
In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.
Identifiants
pubmed: 34344313
doi: 10.1186/s12876-021-01880-9
pii: 10.1186/s12876-021-01880-9
pmc: PMC8336111
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLR Proteins
0
NLRP3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
310Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 3347CO-108792
Investigateurs
Karim Abdelrahman
(K)
Gentiana Ademi
(G)
Patrick Aepli
(P)
Amman Thomas
(A)
Claudia Anderegg
(C)
Anca-Teodora Antonino
(AT)
Eva Archanioti
(E)
Eviano Arrigoni
(E)
Diana Bakker de Jong
(D)
Bruno Balsiger
(B)
Polat Bastürk
(P)
Peter Bauerfeind
(P)
Andrea Becocci
(A)
Dominique Belli
(D)
José M Bengoa
(JM)
Luc Biedermann
(L)
Janek Binek
(J)
Mirjam Blattmann
(M)
Stephan Boehm
(S)
Tujana Boldanova
(T)
Jan Borovicka
(J)
Christian P Braegger
(CP)
Stephan Brand
(S)
Lukas Brügger
(L)
Simon Brunner
(S)
Patrick Bühr
(P)
Bernard Burnand
(B)
Sabine Burk
(S)
Emanuel Burri
(E)
Sophie Buyse
(S)
Dahlia-Thao Cao
(DT)
Ove Carstens
(O)
Dominique H Criblez
(DH)
Sophie Cunningham
(S)
Fabrizia D'Angelo
(F)
Philippe de Saussure
(P)
Lukas Degen
(L)
Joakim Delarive
(J)
Christopher Doerig
(C)
Barbara Dora
(B)
Susan Drerup
(S)
Mara Egger
(M)
Ali El-Wafa
(A)
Matthias Engelmann
(M)
Jessica Ezri
(J)
Christian Felley
(C)
Markus Fliegner
(M)
Nicolas Fournier
(N)
Montserrat Fraga
(M)
Yannick Franc
(Y)
Pascal Frei
(P)
Remus Frei
(R)
Michael Fried
(M)
Florian Froehlich
(F)
Raoul Ivano Furlano
(RI)
Luca Garzoni
(L)
Martin Geyer
(M)
Laurent Girard
(L)
Marc Girardin
(M)
Delphine Golay
(D)
Ignaz Good
(I)
Ulrike Graf Bigler
(U)
Beat Gysi
(B)
Johannes Haarer
(J)
Marcel Halama
(M)
Janine Haldemann
(J)
Pius Heer
(P)
Benjamin Heimgartner
(B)
Beat Helbling
(B)
Peter Hengstler
(P)
Denise Herzog
(D)
Cyrill Hess
(C)
Roxane Hessler
(R)
Klaas Heyland
(K)
Thomas Hinterleitner
(T)
Claudia Hirschi
(C)
Petr Hruz
(P)
Pascal Juillerat
(P)
Carolina Khalid-de Bakker
(C)
Stephan Kayser
(S)
Céline Keller
(C)
Christina Knellwolf-Grieger
(C)
Christoph Knoblauch
(C)
Henrik Köhler
(H)
Rebekka Koller
(R)
Claudia Krieger-Grübel
(C)
Patrizia Künzler
(P)
Rachel Kusche
(R)
Frank Serge Lehmann
(FS)
Andrew Macpherson
(A)
Michel H Maillard
(MH)
Michael Manz
(M)
Astrid Marot
(A)
Rémy Meier
(R)
Christa Meyenberger
(C)
Pamela Meyer
(P)
Pierre Michetti
(P)
Benjamin Misselwitz
(B)
Patrick Mosler
(P)
Christian Mottet
(C)
Christoph Müller
(C)
Beat Müllhaupt
(B)
Leilla Musso
(L)
Michaela Neagu
(M)
Cristina Nichita
(C)
Jan Niess
(J)
Andreas Nydegger
(A)
Nicole Obialo
(N)
Diana Ollo
(D)
Cassandra Oropesa
(C)
Ulrich Peter
(U)
Daniel Peternac
(D)
Laetitia Marie Petit
(LM)
Valérie Pittet
(V)
Daniel Pohl
(D)
Marc Porzner
(M)
Claudia Preissler
(C)
Nadia Raschle
(N)
Ronald Rentsch
(R)
Alexandre Restellini
(A)
Sophie Restellini
(S)
Jean-Pierre Richterich
(JP)
Frederic Ris
(F)
Branislav Risti
(B)
Marc Alain Ritz
(MA)
Gerhard Rogler
(G)
Nina Röhrich
(N)
Jean-Benoît Rossel
(JB)
Vanessa Rueger
(V)
Monica Rusticeanu
(M)
Markus Sagmeister
(M)
Gaby Saner
(G)
Bernhard Sauter
(B)
Mikael Sawatzki
(M)
Michael Scharl
(M)
Martin Schelling
(M)
Susanne Schibli
(S)
Hugo Schlauri
(H)
Dominique Schluckebier
(D)
Daniela Schmid
(D)
Sybille Schmid-Uebelhart
(S)
Jean-François Schnegg
(JF)
Alain Schoepfer
(A)
Vivianne Seematter
(V)
Frank Seibold
(F)
Mariam Seirafi
(M)
Gian-Marco Semadeni
(GM)
Arne Senning
(A)
Christiane Sokollik
(C)
Joachim Sommer
(J)
Johannes Spalinger
(J)
Holger Spangenberger
(H)
Philippe Stadler
(P)
Peter Staub
(P)
Dominic Staudenmann
(D)
Volker Stenz
(V)
Michael Steuerwald
(M)
Alex Straumann
(A)
Bruno Strebel
(B)
Andreas Stulz
(A)
Michael Sulz
(M)
Aurora Tatu
(A)
Michela Tempia-Caliera
(M)
Joël Thorens
(J)
Kaspar Truninger
(K)
Radu Tutuian
(R)
Patrick Urfer
(P)
Stephan Vavricka
(S)
Francesco Viani
(F)
Jürg Vögtlin
(J)
Roland Von Känel
(R)
Dominique Vouillamoz
(D)
Rachel Vulliamy
(R)
Paul Wiesel
(P)
Reiner Wiest
(R)
Stefanie Wöhrle
(S)
Samuel Zamora
(S)
Silvan Zander
(S)
Tina Wylie
(T)
Jonas Zeitz
(J)
Dorothee Zimmermann
(D)
Informations de copyright
© 2021. The Author(s).
Références
Villani AC, Lemire M, Fortin G, et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet. 2009;41:71–6.
pubmed: 19098911
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.
pubmed: 26121197
pmcid: 4519035
Sartor RB. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology. 1994;106:533–9.
pubmed: 8299918
Grottrup-Wolfers E, Moeller J, Karbach U, et al. Elevated cell-associated levels of interleukin 1beta and interleukin 6 in inflamed mucosa of inflammatory bowel disease. Eur J Clin Invest. 1996;26:115–22.
pubmed: 8904520
Mahida YR, Wu K, Jewell DP. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn’s disease. Gut. 1989;30:835–8.
pubmed: 2787769
pmcid: 1434123
Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94:174–81.
pubmed: 8403503
pmcid: 1534387
Guimbaud R, Bertrand V, Chauvelot-Moachon L, et al. Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis. Am J Gastroenterol. 1998;93:2397–404.
pubmed: 9860399
Schreiber S, Nikolaus S, Hampe J, et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet. 1999;353:459–61.
pubmed: 9989717
Bauer C, Duewell P, Mayer C, et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut. 2010;59:1192–9.
pubmed: 20442201
Hirota SA, Ng J, Lueng A, et al. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis. 2011;17:1359–72.
pubmed: 20872834
Itani S, Watanabe T, Nadatani Y, et al. NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis. Sci Rep. 2016;6:39075.
pubmed: 27966619
pmcid: 5155456
Zaki MH, Boyd KL, Vogel P, et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 2010;32:379–91.
pubmed: 20303296
pmcid: 2982187
Paramel Varghese G, Folkersen L, Strawbridge RJ, et al. NLRP3 inflammasome expression and activation in human atherosclerosis. J Am Heart Assoc. 2016;5:e003031.
pubmed: 27207962
pmcid: 4889178
Pittet V, Juillerat P, Mottet C, et al. Cohort profile: the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS). Int J Epidemiol. 2009;38:922–31.
pubmed: 18782896
Pittet V, Michetti P, Mueller C, et al. Cohort profile update: the Swiss inflammatory bowel disease cohort study (SIBDCS). Int J Epidemiol. 2019;48:385–386f.
pubmed: 30689927
Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24.
pubmed: 23128233
pmcid: 3491803
Storm N, Darnhofer-Patel B, van den Boom D, et al. MALDI-TOF mass spectrometry-based SNP genotyping. Methods Mol Biol. 2003;212:241–62.
pubmed: 12491915
Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387:156–67.
pubmed: 26490195
pmcid: 4714968
Endres S, Cannon JG, Ghorbani R, et al. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol. 1989;19:2327–33.
pubmed: 2514105
Nemetz A, Nosti-Escanilla MP, Molnar T, et al. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999;49:527–31.
pubmed: 10380697
Yang CA, Huang ST, Chiang BL. Association of NLRP3 and CARD8 genetic polymorphisms with juvenile idiopathic arthritis in a Taiwanese population. Scand J Rheumatol. 2014;43:146–52.
pubmed: 24295199
Juneblad K, Kastbom A, Johansson L, et al. Association between inflammasome-related polymorphisms and psoriatic arthritis. Scand J Rheumatol. 2021;50:206–12.
pubmed: 33300400
Nemetz A, Kope A, Molnar T, et al. Significant differences in the interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in a Hungarian population with inflammatory bowel disease. Scand J Gastroenterol. 1999;34:175–9.
pubmed: 10192196
Man SM, Hopkins LJ, Nugent E, et al. Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex. Proc Natl Acad Sci U S A. 2014;111:7403–8.
pubmed: 24803432
pmcid: 4034195
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17.
pubmed: 21677747
pmcid: 3204665
Lazaridis LD, Pistiki A, Giamarellos-Bourboulis EJ, et al. Activation of NLRP3 inflammasome in inflammatory bowel disease: differences between Crohn’s disease and ulcerative colitis. Dig Dis Sci. 2017;62:2348–56.
pubmed: 28523573
Mao L, Kitani A, Strober W, et al. The role of NLRP3 and IL-1beta in the pathogenesis of inflammatory bowel disease. Front Immunol. 2018;9:2566.
pubmed: 30455704
pmcid: 6230716
Bauer C, Duewell P, Lehr HA, et al. Protective and aggravating effects of Nlrp3 inflammasome activation in IBD models: influence of genetic and environmental factors. Dig Dis. 2012;30(Suppl 1):82–90.
pubmed: 23075874
Spalinger MR, Kasper S, Gottier C, et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J Clin Invest. 2016;126:4388.
pubmed: 27801679
pmcid: 5096914
Mak'Anyengo R, Duewell P, Reichl C, et al. Nlrp3-dependent IL-1beta inhibits CD103+ dendritic cell differentiation in the gut. JCI Insight 2018;3.
Bersudsky M, Luski L, Fishman D, et al. Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice. Gut. 2014;63:598–609.
pubmed: 23793223
Liu L, Dong Y, Ye M, et al. The pathogenic role of NLRP3 inflammasome activation in inflammatory bowel diseases of both mice and humans. J Crohns Colitis. 2017;11:737–50.
pubmed: 27993998
pmcid: 5881697
Zhang J, Fu S, Sun S, et al. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol. 2014;7:1139–50.
pubmed: 24472848
pmcid: 4115056
Mao L, Kitani A, Similuk M, et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease. J Clin Invest. 2018;128:1793–806.
pubmed: 29408806
pmcid: 5919822
Yao X, Zhang C, Xing Y, et al. Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis. Nat Commun. 2017;8:1896.
pubmed: 29196621
pmcid: 5711854
Yilmaz B, Juillerat P, Oyas O, et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat Med. 2019;25:323–36.
pubmed: 30664783
O’Donnell S, Borowski K, Espin-Garcia O, et al. The Unsolved link of genetic markers and Crohn’s disease progression: a North American cohort experience. Inflamm Bowel Dis. 2019;25:1541–9.
pubmed: 30801121
Lee JC, Biasci D, Roberts R, et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nat Genet. 2017;49:262–8.
pubmed: 28067912
pmcid: 5730041
Pierik M, Joossens S, Van Steen K, et al. Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis. 2006;12:1–8.
pubmed: 16374251
Lang BM, Biedermann L, van Haaften WT, et al. Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn’s disease. Aliment Pharmacol Ther. 2018;47:55–66.
pubmed: 29052254
Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.
pubmed: 25686105
pmcid: 4392179
Jiang H, He H, Chen Y, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017;214:3219–38.
pubmed: 29021150
pmcid: 5679172