The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_E3808C2BBE14
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.
Journal
BMC gastroenterology
Author(s)
Tcymbarevich I.V., Eloranta J.J., Rossel J.B., Obialo N., Spalinger M., Cosin-Roger J., Lang S., Kullak-Ublick G.A., Wagner C.A., Scharl M., Seuwen K., Ruiz P.A., Rogler G., de Vallière C., Misselwitz B.
Working group(s)
Swiss IBD Cohort Study Group
Contributor(s)
Abdelrahman K., Ademi G., Aepli P., Thomas A., Anderegg C., Antonino A.T., Archanioti E., Arrigoni E., de Jong D.B., Balsiger B., Bastürk P., Bauerfeind P., Becocci A., Belli D., Bengoa J.M., Biedermann L., Binek J., Blattmann M., Boehm S., Boldanova T., Borovicka J., Braegger C.P., Brand S., Brügger L., Brunner S., Bühr P., Burnand B., Burk S., Burri E., Buyse S., Cao D.T., Carstens O., Criblez D.H., Cunningham S., D'Angelo F., de Saussure P., Degen L., Delarive J., Doerig C., Dora B., Drerup S., Egger M., El-Wafa A., Engelmann M., Ezri J., Felley C., Fliegner M., Fournier N., Fraga M., Franc Y., Frei P., Frei R., Fried M., Froehlich F., Furlano R.I., Garzoni L., Geyer M., Girard L., Girardin M., Golay D., Good I., Bigler U.G., Gysi B., Haarer J., Halama M., Haldemann J., Heer P., Heimgartner B., Helbling B., Hengstler P., Herzog D., Hess C., Hessler R., Heyland K., Hinterleitner T., Hirschi C., Hruz P., Juillerat P., Bakker C.K., Kayser S., Keller C., Knellwolf C., Knoblauch C., Köhler H., Koller R., Krieger C., Künzler P., Kusche R., Lehmann F.S., Macpherson A., Maillard M.H., Manz M., Marot A., Meier R., Meyenberger C., Meyer P., Michetti P., Misselwitz B., Mosler P., Mottet C., Müller C., Müllhaupt B., Musso L., Neagu M., Nichita C., Niess J., Nydegger A., Obialo N., Ollo D., Oropesa C., Peter U., Peternac D., Petit L.M., Pittet V., Pohl D., Porzner M., Preissler C., Raschle N., Rentsch R., Restellini A., Restellini S., Richterich J.P., Ris F., Risti B., Ritz M.A., Rogler G., Röhrich N., Rossel J.B., Rueger V., Rusticeanu M., Sagmeister M., Saner G., Sauter B., Sawatzki M., Scharl M., Schelling M., Schibli S., Schlauri H., Schluckebier D., Schmid D., Schmid S., Schnegg J.F., Schoepfer A., Seematter V., Seibold F., Seirafi M., Semadeni G.M., Senning A., Sokollik C., Sommer J., Spalinger J., Spangenberger H., Stadler P., Staub P., Staudenmann D., Stenz V., Steuerwald M., Straumann A., Strebel B., Stulz A., Sulz M., Tatu A., Tempia-Caliera M., Thorens J., Truninger K., Tutuian R., Urfer P., Vavricka S., Viani F., Vögtlin J., Von Känel R., Vouillamoz D., Vulliamy R., Wiesel P., Wiest R., Wöhrle S., Zamora S., Zander S., Wylie T., Zeitz J., Zimmermann D.
ISSN
1471-230X (Electronic)
ISSN-L
1471-230X
Publication state
Published
Issued date
07/01/2019
Peer-reviewed
Oui
Volume
19
Number
1
Pages
2
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
Adult, Alleles, Cyclic AMP/blood, Female, Galactosylceramidase/genetics, Genetic Predisposition to Disease, Genotype, Homozygote, Humans, Hydrogen-Ion Concentration, Inflammatory Bowel Diseases/genetics, Inflammatory Bowel Diseases/physiopathology, Lipopolysaccharide Receptors, Macrophages/immunology, Macrophages/metabolism, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled/genetics, Receptors, G-Protein-Coupled/physiology, Risk Factors, Signal Transduction, rhoA GTP-Binding Protein/blood, Acidic pH, CD, IBD, Inflammatory bowel diseases, RhoA, UC, cAMP, pH-sensing
Pubmed
Web of science
Open Access
Yes
Create date
14/01/2019 17:29
Last modification date
20/08/2019 17:07
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