The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation
Abstract 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 activatio...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | BMC Gastroenterology |
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| Online Access: | http://link.springer.com/article/10.1186/s12876-018-0922-8 |
| _version_ | 1818413102481276928 |
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| author | Irina V. Tcymbarevich Jyrki J. Eloranta Jean-Benoît Rossel Nicole Obialo Marianne Spalinger Jesus Cosin-Roger Silvia Lang Gerd A. Kullak-Ublick Carsten A. Wagner Michael Scharl Klaus Seuwen Pedro A. Ruiz Gerhard Rogler Cheryl de Vallière Benjamin Misselwitz on behalf of the Swiss IBD Cohort Study Group |
| author_facet | Irina V. Tcymbarevich Jyrki J. Eloranta Jean-Benoît Rossel Nicole Obialo Marianne Spalinger Jesus Cosin-Roger Silvia Lang Gerd A. Kullak-Ublick Carsten A. Wagner Michael Scharl Klaus Seuwen Pedro A. Ruiz Gerhard Rogler Cheryl de Vallière Benjamin Misselwitz on behalf of the Swiss IBD Cohort Study Group |
| author_sort | Irina V. Tcymbarevich |
| collection | DOAJ |
| description | Abstract 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 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 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 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. |
| first_indexed | 2024-12-14T10:57:52Z |
| format | Article |
| id | doaj.art-6941ccbb826442539db66cc0037811fa |
| institution | Directory Open Access Journal |
| issn | 1471-230X |
| language | English |
| last_indexed | 2024-12-14T10:57:52Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Gastroenterology |
| spelling | doaj.art-6941ccbb826442539db66cc0037811fa2022-12-21T23:04:51ZengBMCBMC Gastroenterology1471-230X2019-01-0119111110.1186/s12876-018-0922-8The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammationIrina V. Tcymbarevich0Jyrki J. Eloranta1Jean-Benoît Rossel2Nicole Obialo3Marianne Spalinger4Jesus Cosin-Roger5Silvia Lang6Gerd A. Kullak-Ublick7Carsten A. Wagner8Michael Scharl9Klaus Seuwen10Pedro A. Ruiz11Gerhard Rogler12Cheryl de Vallière13Benjamin Misselwitz14on behalf of the Swiss IBD Cohort Study GroupDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichClinical Pharmacology and Toxicology, University Hospital Zurich, University of ZurichInsitute of Social and Preventative MedicineDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichClinical Pharmacology and Toxicology, University Hospital Zurich, University of ZurichInstitute of Physiology, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichNovartis Institutes for Biomedical ResearchDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichDepartment of Gastroenterology and Hepatology, University Hospital Zurich, University of ZurichAbstract 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 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 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 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.http://link.springer.com/article/10.1186/s12876-018-0922-8pH-sensingRhoAAcidic pHcAMPInflammatory bowel diseasesIBD |
| spellingShingle | Irina V. Tcymbarevich Jyrki J. Eloranta Jean-Benoît Rossel Nicole Obialo Marianne Spalinger Jesus Cosin-Roger Silvia Lang Gerd A. Kullak-Ublick Carsten A. Wagner Michael Scharl Klaus Seuwen Pedro A. Ruiz Gerhard Rogler Cheryl de Vallière Benjamin Misselwitz on behalf of the Swiss IBD Cohort Study Group The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation BMC Gastroenterology pH-sensing RhoA Acidic pH cAMP Inflammatory bowel diseases IBD |
| title | The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation |
| title_full | The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation |
| title_fullStr | The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation |
| title_full_unstemmed | The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation |
| title_short | The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation |
| title_sort | impact of the rs8005161 polymorphism on g protein coupled receptor gpr65 tdag8 ph associated activation in intestinal inflammation |
| topic | pH-sensing RhoA Acidic pH cAMP Inflammatory bowel diseases IBD |
| url | http://link.springer.com/article/10.1186/s12876-018-0922-8 |
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