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Analysis of GPRC6A variants in different pancreatitis etiologies.

Department of Internal Medicine I, Martin Luther University, Halle, Germany. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHRU Brest, Service de Génétique Médicale et de Biologie de la Reproduction, Brest, France. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France. Department of Gastroenterology and Pancreatology, Beaujon Hospital, APHP, Clichy, and Paris-Diderot University, Paris, France. Service de Gastroentérologie et Pancréatologie, CHU Toulouse, Toulouse, France. Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Chirurgische Klinik, Erlangen, Germany. Department of Gastroenterology and Hepatology, Radboud umc, Nijmegen, the Netherlands. Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy. Department of Internal Medicine and Gastroenterology, University of Medicine and Pharmacy, Craiova, Romania. Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland. Collegium Medicum (Medical College), Jan Kochanowski University, Kielce, Poland. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany. Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. Institute for Translational Medicine and First Department of Internal Medicine, Medical School, University of Pécs, Pécs, Hungary; First Department of Medicine, University of Szeged, Szeged, Hungary. Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany. Department of Internal Medicine I, Martin Luther University, Halle, Germany. Electronic address: jonas.rosendahl@uk-halle.de.

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2020;(7):1262-1267
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Abstract

BACKGROUND The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10-5) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.