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1. Cohort profile: the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS)

Author

Pittet, V, Juillerat, P, Mottet, C, Felley, C, Ballabeni, P, Burnand, B, Michetti, P, Vader, JP, and, the Swiss IBD Cohort Study Group, Swiss IBD Cohort Study Group, Michetti, P., Vader, JP., Burnand, B., Pittet, V., Ballabeni, P., Mueller, C., Rihs, S., Braegger, C., Mottet, C., Juillerat, P., Felley, C., Beglinger, C., Froehlich, F., Vavricka, S., Seibold, F., Schoepfer, A., von Känel, R., Begré, S., de Saussure, P., Meyenberger, C., Sagmeister, M., Rogler, G., Kullak-Ublick, GA., Meier, R., Straumann, A., Criblez, D., Engelmann, M., Schenk, M., University of Zurich, and Pittet, V

Subjects
medicine.medical_specialty, Pediatrics, Biological Specimen Banks, Cohort Studies, Humans, Inflammatory Bowel Diseases/epidemiology, Inflammatory Bowel Diseases/etiology, Patient Dropouts/statistics & numerical data, Patient Selection, Risk Factors, Switzerland/epidemiology, Patient Dropouts, Epidemiology, 610 Medicine & health, Disease, Inflammatory bowel disease, 03 medical and health sciences, Indirect costs, 0302 clinical medicine, Medicine, business.industry, General Medicine, medicine.disease, Inflammatory Bowel Diseases, Family life, 3. Good health, Surgery, 10219 Clinic for Gastroenterology and Hepatology, 10036 Medical Clinic, 030220 oncology & carcinogenesis, Cohort, Absenteeism, 030211 gastroenterology & hepatology, business, Switzerland, Cohort study, 2713 Epidemiology
Abstract

already in the first or second decade of life, while patients are either in full-time education or just entering the workforce. The negative impact on social life or ability to achieve, either scholastically or professionally, can severely affect professional as well as family life. Indeed, 450% of patients with Crohn’s disease indicate that their disease has an influence on their professional and personal life. 6 The course of the disease is often characterized by progressive worsening of the patient’s condition, with increasing frequency of hospitalization and considerable indirect costs through absenteeism and disability allowances. 7 Disease activity is known to be

Published
2009
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3. Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort

Author

Pittet, V, Juillerat, P, Michetti, P, Vader, J P, Burnand, B, Rogler, G, Beglinger, C, Seibold, F, Mottet, C, Felley, C, Gonvers, J J, Froehlich, F, et al, Braegger, C P, University of Zurich, and Pittet, V

Subjects
10036 Medical Clinic, 2736 Pharmacology (medical), 610 Medicine & health, 2721 Hepatology, 2715 Gastroenterology
Published
2010
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4. Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease

Author

Vavricka, S R, Spigaglia, S M, Rogler, G, Pittet, V, Michetti, P, Felley, C, Mottet, C, Braegger, C P, Rogler, D, Straumann, A, Bauerfeind, P, Fried, M, Schoepfer, A M, University of Zurich, and Vavricka, S R

Subjects
10219 Clinic for Gastroenterology and Hepatology, 10036 Medical Clinic, 10076 Center for Integrative Human Physiology, 2723 Immunology and Allergy, 570 Life sciences, biology, 610 Medicine & health, 2715 Gastroenterology
Published
2011

8. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease

Author

Fournier, N, Vavricka, S R, Juillerat, Pascal, Rogler, G, Straumann, A, Schoepfer, A M, Swiss IBD Cohort, Study Group, Safroneeva, Ekaterina, Pittet, V, and Peyrin-Biroulet, L

Subjects
610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

BACKGROUND The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.

9. The personality traits activity, self-reproach, and negative affect jointly predict clinical recurrence, depressive symptoms, and low quality of life in inflammatory bowel disease patients

Author

Sebastian Bruno Ulrich, Jordi, Brian Matthew, Lang, Jacqueline, Wyss, Bianca, Auschra, Bahtiyar, Yilmaz, Niklas, Krupka, Thomas, Greuter, Philipp, Schreiner, Luc, Biedermann, Martin, Preisig, Roland, von Känel, Gerhard, Rogler, Stefan, Begré, Benjamin, Misselwitz, Dorothee, Zimmermann, Swiss IBD cohort study group, Anderegg, C., Bauerfeind, P., Beglinger, C., Begré, S., Belli, D., Bengoa, J.M., Biedermann, L., Bigler, B., Binek, J., Blattmann, M., Boehm, S., Borovicka, J., Braegger, C.P., Brunner, N., Bühr, P., Burnand, B., Burri, E., Buyse, S., Cremer, M., Criblez, D.H., de Saussure, P., Degen, L., Delarive, J., Doerig, C., Dora, B., Dorta, G., Egger, M., Ehmann, T., El-Wafa, A., Engelmann, M., Ezri, J., Felley, C., Fliegner, M., Fournier, N., Fraga, M., Frei, P., Frei, R., Fried, M., Froehlich, F., Funk, C., Furlano, R.I., Gallot-Lavallée, S., Geyer, M., Girardin, M., Golay, D., Grandinetti, T., Gysi, B., Haack, H., Haarer, J., Helbling, B., Hengstler, P., Herzog, D., Hess, C., Heyland, K., Hinterleitner, T., Hiroz, P., Hirschi, C., Hruz, P., Iwata, R., Jost, R., Juillerat, P., Brondolo, V.K., Knellwolf, C., Knoblauch, C., Köhler, H., Koller, R., Krieger-Grübel, C., Kullak-Ublick, G., Künzler, P., Landolt, M., Lange, R., Lehmann, F.S., Macpherson, A., Maerten, P., Maillard, M.H., Manser, C., Manz, M., Marbet, U., Marx, G., Matter, C., McLin, V., Meier, R., Mendanova, M., Meyenberger, C., Michetti, P., Misselwitz, B., Moradpour, D., Morell, B., Mosler, P., Mottet, C., Müller, C., Müller, P., Müllhaupt, B., Münger-Beyeler, C., Musso, L., Nagy, A., Neagu, M., Nichita, C., Niess, J., Noël, N., Nydegger, A., Obialo, N., Oneta, C., Oropesa, C., Peter, U., Peternac, D., Petit, L.M., Piccoli-Gfeller, F., Pilz, J.B., Pittet, V., Raschle, N., Rentsch, R., Restellini, S., Richterich, J.P., Rihs, S., Ritz, M.A., Roduit, J., Rogler, D., Rogler, G., Rossel, J.B., Sagmeister, M., Saner, G., Sauter, B., Sawatzki, M., Schäppi, M., Scharl, M., Schelling, M., Schibli, S., Schlauri, H., Uebelhart, S.S., Schnegg, J.F., Schoepfer, A., Seibold, F., Seirafi, M., Semadeni, G.M., Semela, D., Senning, A., Sidler, M., Sokollik, C., Spalinger, J., Spangenberger, H., Stadler, P., Steuerwald, M., Straumann, A., Straumann-Funk, B., Sulz, M., Thorens, J., Tiedemann, S., Tutuian, R., Vavricka, S., Viani, F., Vögtlin, J., von Känel, R., Vonlaufen, A., Vouillamoz, D., Vulliamy, R., Wermuth, J., Werner, H., Wiesel, P., Wiest, R., Wylie, T., Zeitz, J., and Zimmermann, D.

Subjects
Cohort Studies, Humans, Personality Inventory, Quality of Life, Depression/epidemiology, Personality, Chronic Disease, Inflammatory Bowel Diseases, Five-factor model, Flares, IBD, NEO-FFI, Depression, Gastroenterology, 610 Medicine & health
Abstract

Background The bidirectional “gut-brain axis” has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). While the influence of stress and depressive symptoms on IBD is well-characterized, the role of personality remains insufficiently investigated. Methods Personality was assessed in 1154 Swiss IBD cohort study (SIBDCS) patients via the NEO-Five-Factor Inventory (NEO-FFI) as well as in 2600 participants of the population-based CoLaus¦PsyCoLaus cohort study (NEO-FFI-revised). The NEO-FFI subcomponents activity, self-reproach and negative affect were associated with higher IBD disease activity and were combined to a NEO-FFI risk score. This risk score was validated and its effect on clinical IBD course and psychological endpoints was analysed in time-to-event and cumulative incidence analyses. Results In time-to-event analyses, a high NEO-FFI risk score was predictive for the clinical endpoints of new extraintestinal manifestation [EIM, adjusted hazard ratio (aHR) = 1.64, corrected p value (q) = 0.036] and two established composite flare endpoints (aHR = 1.53–1.63, q = 0.003–0.006) as well as for the psychological endpoints depressive symptoms (aHR = 7.06, q q r = 0.03–0.14). Conclusions Personality assessed by the NEO-FFI contained considerable predictive power for disease recurrence, depressive symptoms and low quality of life in IBD patients. Nevertheless, the personalities of IBD patients did not substantially differ from the general population.

Published
2022

10. Genotype–phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients

Author

Yoganathan, Priyatharsan, Rossel, Jean-Benoit, Jordi, Sebastian Bruno Ulrich, Franc, Yannick, Biedermann, Luc, Misselwitz, Benjamin, Hausmann, Martin, Rogler, Gerhard, Scharl, Michael, Frey-Wagner, Isabelle, Swiss IBD cohort study group, Marot, Astrid, Ris, Frédéric, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, University of Zurich, Frey-Wagner, Isabelle, Swiss IBD cohort study group, 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., Grieger, C.K., Knoblauch, C., Köhler, H., Koller, R., Krieger-Grübel, 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., Uebelhart, S.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., and Zimmermann, D.

Subjects
Genotype, NLR Proteins, 610 Medicine & health, Single-nucleotide polymorphism, RC799-869, Disease, Polymorphism, Single Nucleotide, Inflammatory bowel disease, Pyrin domain, Cohort Studies, NLR Family, Pyrin Domain-Containing 3 Protein, Genetic variation, medicine, Humans, 2715 Gastroenterology, Genetic Predisposition to Disease, Allele, Gene, Genetic Association Studies, integumentary system, ddc:617, Clinical characteristics, 10179 Institute of Medical Microbiology, business.industry, Gastroenterology, Pyrin Domain, Single nucleotide polymorphisms, General Medicine, Diseases of the digestive system. Gastroenterology, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, Colitis, Ulcerative/genetics, Switzerland, NLRP3 inflammasome, 10219 Clinic for Gastroenterology and Hepatology, 10036 Medical Clinic, Immunology, Colitis, Ulcerative, 610 Medizin und Gesundheit, business, Research Article
Abstract

Background Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn’s Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). Methods We included 981 Crohn’s disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. Results In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. Conclusions In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.

Published
2021

11. Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management

Author

Luc Biedermann, Alexander Siebenhüner, Philipp Schreiner, René Roth, Benjamin Misselwitz, Martina Ledergerber, Brian M. Lang, Niklas Krupka, Thomas Greuter, Henriette Heinrich, Stefan Begré, Andreas Rickenbacher, Stephan R. Vavricka, Jonas Zeitz, Matthias Turina, Niko Beerenwinkel, Gerhard Rogler, Swiss IBD Cohort Study Group, Anderegg, C., Bauerfeind, P., Beglinger, C., Begré, S., Belli, D., Bengoa, J.M., Biedermann, L., Bigler, B., Binek, J., Blattmann, M., Boehm, S., Borovicka, J., Braegger, C.P., Brunner, N., Bühr, P., Burnand, B., Burri, E., Buyse, S., Cremer, M., Criblez, D.H., de Saussure, P., Degen, L., Delarive, J., Doerig, C., Dora, B., Dorta, G., Egger, M., Ehmann, T., El-Wafa, A., Engelmann, M., Ezri, J., Felley, C., Fliegner, M., Fournier, N., Fraga, M., Frei, P., Frei, R., Fried, M., Froehlich, F., Funk, C., Furlano, R.I., Gallot-Lavallée, S., Geyer, M., Girardin, M., Golay, D., Grandinetti, T., Gysi, B., Haack, H., Haarer, J., Helbling, B., Hengstler, P., Herzog, D., Hess, C., Heyland, K., Hinterleitner, T., Hiroz, P., Hirschi, C., Hruz, P., Iwata, R., Jost, R., Juillerat, P., Brondolo, V.K., Knellwolf, C., Knoblauch, C., Köhler, H., Koller, R., Krieger-Grübel, C., Kullak-Ublick, G., Künzler, P., Landolt, M., Lange, R., Lehmann, F.S., Macpherson, A., Maerten, P., Maillard, M.H., Manser, C., Manz, M., Marbet, U., Marx, G., Matter, C., McLin, V., Meier, R., Mendanova, M., Meyenberger, C., Michetti, P., Misselwitz, B., Moradpour, D., Morell, B., Mosler, P., Mottet, C., Müller, C., Müller, P., Müllhaupt, B., Münger-Beyeler, C., Musso, L., Nagy, A., Neagu, M., Nichita, C., Niess, J., Noël, N., Nydegger, A., Obialo, N., Oneta, C., Oropesa, C., Peter, U., Peternac, D., Petit, L.M., Piccoli-Gfeller, F., Pilz, J.B., Pittet, V., Raschle, N., Rentsch, R., Restellini, S., Richterich, J.P., Rihs, S., Ritz, M.A., Roduit, J., Rogler, D., Rogler, G., Rossel, J.B., Sagmeister, M., Saner, G., Sauter, B., Sawatzki, M., Schäppi, M., Scharl, M., Schelling, M., Schibli, S., Schlauri, H., Uebelhart, S.S., Schnegg, J.F., Schoepfer, A., Seibold, F., Seirafi, M., Semadeni, G.M., Semela, D., Senning, A., Sidler, M., Sokollik, C., Spalinger, J., Spangenberger, H., Stadler, P., Steuerwald, M., Straumann, A., Straumann-Funk, B., Sulz, M., Thorens, J., Tiedemann, S., Tutuian, R., Vavricka, S., Viani, F., Vögtlin, J., Von Känel, R., Vonlaufen, A., Vouillamoz, D., Vulliamy, R., Wermuth, J., Werner, H., Wiesel, P., Wiest, R., Wylie, T., Zeitz, J., Zimmermann, D., University of Zurich, and Misselwitz, Benjamin

Subjects
0301 basic medicine, Crohn’s disease, Abdominal pain, medicine.medical_specialty, 610 Medicine & health, Disease, Polymorphism, Single Nucleotide, Inflammatory bowel disease, Gastroenterology, Single-nucleotide polymorphisms, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Abdominal Pain/genetics, Colitis, Ulcerative/complications, Colitis, Ulcerative/genetics, Humans, Inflammatory Bowel Diseases/complications, Inflammatory Bowel Diseases/genetics, Irritable Bowel Syndrome/complications, Irritable Bowel Syndrome/genetics, Nucleotides, Irritable bowel syndrome, Ulcerative colitis, Internal medicine, medicine, 2715 Gastroenterology, lcsh:RC799-869, 10217 Clinic for Visceral and Transplantation Surgery, Crohn's disease, business.industry, General Medicine, Hepatology, Inflammatory Bowel Diseases, medicine.disease, 10219 Clinic for Gastroenterology and Hepatology, 030104 developmental biology, 10036 Medical Clinic, Colitis, Ulcerative, 030211 gastroenterology & hepatology, lcsh:Diseases of the digestive system. Gastroenterology, medicine.symptom, 610 Medizin und Gesundheit, business, Research Article, Cohort study
Abstract

Background Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear. Methods Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models. Results In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P, BMC Gastroenterology, 21 (1), ISSN:1471-230X

Published
2021

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

Author

Tcymbarevich, Irina V, Eloranta, Jyrki J, Rossel, Jean-Benoît, Obialo, Nicole, Spalinger, Marianne, Cosin-Roger, Jesus, Lang, Silvia, Kullak-Ublick, Gerd A, Wagner, Carsten A, Scharl, Michael, Seuwen, Klaus, Ruiz, Pedro A, Rogler, Gerhard, de Vallière, Cheryl, Misselwitz, Benjamin, Swiss IBD Cohort Study Group, Marot, Astrid, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, University of Zurich, de Vallière, Cheryl, Petit, Laëtitia Marie, Swiss IBD Cohort Study Group, 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., and Zimmermann, D.

Subjects
Male, RHOA, pH-sensing, Lipopolysaccharide Receptors, 10052 Institute of Physiology, Receptors, G-Protein-Coupled, 0302 clinical medicine, UC, Risk Factors, Genotype, Adult, Alleles, Cyclic AMP/blood, Female, Galactosylceramidase/genetics, Genetic Predisposition to Disease, Homozygote, Humans, Hydrogen-Ion Concentration, Inflammatory Bowel Diseases/genetics, Inflammatory Bowel Diseases/physiopathology, Macrophages/immunology, Macrophages/metabolism, Middle Aged, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled/genetics, Receptors, G-Protein-Coupled/physiology, Signal Transduction, rhoA GTP-Binding Protein/blood, Acidic pH, CD, IBD, Inflammatory bowel diseases, RhoA, cAMP, Cyclic AMP, Receptor, ddc:618, biology, Gastroenterology, General Medicine, 3. Good health, 10219 Clinic for Gastroenterology and Hepatology, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Research Article, Galactosylceramidase, medicine.medical_specialty, CD14, Single-nucleotide polymorphism, 610 Medicine & health, 03 medical and health sciences, Internal medicine, medicine, Extracellular, SNP, 2715 Gastroenterology, Allele, lcsh:RC799-869, business.industry, Macrophages, digestive system diseases, Endocrinology, 10036 Medical Clinic, 10199 Clinic for Clinical Pharmacology and Toxicology, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, business, rhoA GTP-Binding Protein
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. Electronic supplementary material The online version of this article (10.1186/s12876-018-0922-8) contains supplementary material, which is available to authorized users.

Published
2019

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