The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation
Por:
Tcymbarevich, I, Eloranta, J, Spalinger, M, Cosin-Roger, J, Lang, S, Kullak-Ublick, G, Wagner, C, Seuwen, K, Ruiz, P, de Valliere, C, Abdelrahman, K, Ademi, G, Aepli, P, Thomas, A, Anderegg, C, Antonino, A, Archanioti, E, Arrigoni, E, de Jong, D, Balsiger, B, Basturk, P, Bauerfeind, P, Becocci, A, Belli, D, Bengoa, J, Biedermann, L, Binek, J, Blattmann, M, Boehm, S, Boldanova, T, Borovicka, J, Braegger, C, Brand, S, Brugger, L, Brunner, S, Buhr, P, Burnand, B, Burk, S, Burri, E, Buyse, S, Cao, D, Carstens, O, Criblez, D, 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, Garzoni, L, Geyer, M, Girard, L, Girardin, M, Golay, D, Good, I, Bigler, U, 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, Khalid-de Bakker, C, Kayser, S, Keller, C, Knellwolf-Grieger, C, Knoblauch, C, Kohler, H, Koller, R, Krieger-Grubel, C, Kunzler, P, Kusche, R, Lehmann, F, Macpherson, A, Maillard, M, Manz, M, Marot, A, Meier, R, Meyenberger, C, Meyer, P, Michetti, P, Misselwitz, B, Mosler, P, Mottet, C, Muller, C, Mullhaupt, B, Musso, L, Neagu, M, Nichita, C, Niess, J, Nydegger, A, Obialo, N, Ollo, D, Oropesa, C, Peter, U, Peternac, D, Petit, L, Pittet, V, Pohl, D, Porzner, M, Preissler, C, Raschle, N, Rentsch, R, Restellini, A, Restellini, S, Richterich, J, Ris, F, Risti, B, Ritz, M, Rogler, G, Rohrich, N, Rossel, J, 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-Uebelhart, S, Schnegg, J, Schoepfer, A, Seematter, V, Seibold, F, Seirafi, M, Semadeni, G, 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, Vogtlin, J, Von Kanel, R, Vouillamoz, D, Vulliamy, R, Wiesel, P, Wiest, R, Wohrle, S, Zamora, S, Zander, S, Wylie, T, Zeitz, J, Zimmermann, D and Swiss IBD Cohort Study Grp
Publicada:
7 ene 2019
Resumen:
BackgroundTissue 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.Methods1138 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.ResultsIn 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.ConclusionsThe 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.
Filiaciones:
Tcymbarevich, I:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Eloranta, J:
Univ Zurich, Univ Hosp Zurich, Clin Pharmacol & Toxicol, Zurich, Switzerland
Spalinger, M:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Lang, S:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Kullak-Ublick, G:
Univ Zurich, Univ Hosp Zurich, Clin Pharmacol & Toxicol, Zurich, Switzerland
Wagner, C:
Univ Zurich, Inst Physiol, Zurich, Switzerland
Seuwen, K:
Novartis Inst Biomed Res, Basel, Switzerland
Ruiz, P:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
de Valliere, C:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Misselwitz, B:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Inselspital Bern, Dept Viceral Surg & Med, Freiburgstr 18, CH-3010 Bern, Switzerland
Univ Bern, Freiburgstr 18, CH-3010 Bern, Switzerland
Obialo, N:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Rogler, G:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Rossel, J:
Inst Social & Preventat Med, Lausanne, Switzerland
Scharl, M:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland
Green Published, Green Accepted, gold
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