The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.
Adult
Alleles
Cyclic AMP
/ blood
Female
Galactosylceramidase
/ genetics
Genetic Predisposition to Disease
Genotype
Homozygote
Humans
Hydrogen-Ion Concentration
Inflammatory Bowel Diseases
/ genetics
Lipopolysaccharide Receptors
Macrophages
/ immunology
Male
Middle Aged
Polymorphism, Single Nucleotide
Receptors, G-Protein-Coupled
/ genetics
Risk Factors
Signal Transduction
rhoA GTP-Binding Protein
/ blood
Acidic pH
CD
IBD
Inflammatory bowel diseases
RhoA
UC
cAMP
pH-sensing
Journal
BMC gastroenterology
ISSN: 1471-230X
Titre abrégé: BMC Gastroenterol
Pays: England
ID NLM: 100968547
Informations de publication
Date de publication:
07 Jan 2019
07 Jan 2019
Historique:
received:
07
12
2017
accepted:
20
12
2018
entrez:
9
1
2019
pubmed:
9
1
2019
medline:
1
2
2019
Statut:
epublish
Résumé
Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161. 1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured. In our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele. The T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.
Sections du résumé
BACKGROUND
BACKGROUND
Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161.
METHODS
METHODS
1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured.
RESULTS
RESULTS
In our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele.
CONCLUSIONS
CONCLUSIONS
The T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.
Identifiants
pubmed: 30616622
doi: 10.1186/s12876-018-0922-8
pii: 10.1186/s12876-018-0922-8
pmc: PMC6323805
doi:
Substances chimiques
GPR65 protein, human
0
Lipopolysaccharide Receptors
0
Receptors, G-Protein-Coupled
0
RHOA protein, human
124671-05-2
Cyclic AMP
E0399OZS9N
Galactosylceramidase
EC 3.2.1.46
rhoA GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 153380
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 32473B_156525
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CH)
ID : 33CS30_148422
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
(DB)
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
(UG)
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
(CK)
Stephan Kayser
(S)
Céline Keller
(C)
Christina Knellwolf
(C)
Christoph Knoblauch
(C)
Henrik Köhler
(H)
Rebekka Koller
(R)
Claudia Krieger
(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
(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)
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