Abstract
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.
Highlights
Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH
Three G protein-coupled receptors (GPCR), T cell death-associated gene 8 (TDAG8 known as G-protein-coupled receptor 65 (GPR65)), ovarian cancer G protein-coupled receptor 1 (OGR1 known as GPR68) and G protein coupled receptor 4 (GPR4), have been shown to sense extracellular protons and stimulate a variety of signalling pathways [5,6,7,8,9]
The possible association of the T allele of rs8005161 with Ulcerative colitis (UC) in our initial cohort could not be confirmed with Swiss IBD cohort (SIBDC) data
Summary
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. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Three G protein-coupled receptors (GPCR), T cell death-associated gene 8 (TDAG8 known as GPR65), ovarian cancer G protein-coupled receptor 1 (OGR1 known as GPR68) and G protein coupled receptor 4 (GPR4), have been shown to sense extracellular protons and stimulate a variety of signalling pathways [5,6,7,8,9]. Accumulating evidence indicates that these particular proton-sensing receptors play a crucial role in pH homeostasis [6, 8, 10,11,12]
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