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

TitleThe impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.
Publication TypeJournal Article
Year of Publication2019
AuthorsTcymbarevich, IV, Eloranta, JJ, Rossel, J-B, Obialo, N, Spalinger, M, Cosin-Roger, J, Lang, S, Kullak-Ublick, GA, Wagner, CA, Scharl, M, Seuwen, K, Ruiz, PA, Rogler, G, de Vallière, C, Misselwitz, B
Corporate AuthorsGroup, SIBDCohort
JournalBMC gastroenterology
Volume19
Issue1
Pagination2
Date Published01/2019
DOI10.1186/s12876-018-0922-8
ISSN1471-230X
KeywordsAdult, Alleles, Cyclic AMP, Female, Galactosylceramidase, Genetic Predisposition to Disease, Genotype, Homozygote, Humans, Hydrogen-Ion Concentration, Inflammatory Bowel Diseases, Lipopolysaccharide Receptors, Macrophages, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, rhoA GTP-Binding Protein, Risk Factors, Signal Transduction
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.

Alternate URL

https://www.ncbi.nlm.nih.gov/pubmed/30616622?dopt=Abstract

WOS ID (UT)

000455096600001

Alternate JournalBMC Gastroenterol
Citation Key / SERVAL ID9576
Peer reviewRefereed
PubMed ID30616622
PubMed Central IDPMC6323805
Grant List153380 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung /
32473B_156525 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung /
33CS30_148422 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CH) /

                         

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