- Fecal Incontinence
|The serotonin receptor 3E variant is a risk factor for female IBS-D
J Mol Med (Berl). 2022 Nov;100(11):1617-1627.doi: 10.1007/s00109-022-02244-w. Epub 2022 Sep 19.
Nikola Fritz 1, Sabrina Berens 2, Yuanjun Dong 1, Cristina Martínez 1 3 4, Stefanie Schmitteckert 5, Lesley A Houghton 6 7, Miriam Goebel-Stengel 8 9, Verena Wahl 1, Maria Kabisch 10, Dorothea Götze 1, Mauro D'Amato 11 12 13, Tenghao Zheng 11, Ralph Röth 1 14, Hubert Mönnikes 15, Jonas Tesarz 2, Felicitas Engel 2, Annika Gauss 16, Martin Raithel 17, Viola Andresen 18, Jutta Keller 18, Thomas Frieling 19, Christian Pehl 20, Christoph Stein-Thöringer 21, Gerard Clarke 22 23, Paul J Kennedy 22 23, John F Cryan 22 23 24, Timothy G Dinan 22 23, Eamonn M M Quigley 23 25, Robin Spiller 26, Caroll Beltrán 27, Ana María Madrid 27, Verónica Torres 27, Emeran A Mayer 28, Gregory Sayuk 29, Maria Gazouli 30, George Karamanolis 31, Mariona Bustamante 32 33, Xavier Estivil 34, Raquel Rabionet 34, Per Hoffmann 35, Markus M Nöthen 35, Stefanie Heilmann-Heimbach 35, Börge Schmidt 36, André Franke 37, Wolfgang Lieb 38, Wolfgang Herzog 2, Guy Boeckxstaens 39, Mira M Wouters 39, Magnus Simrén 40, Gudrun A Rappold 1 41, Maria Vicario 42 43, Javier Santos 42, Rainer Schaefert 44 45, Justo Lorenzo-Bermejo 10, Beate Niesler 1 14 41
1Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
2Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany.
3Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain.
4Lleida Institute for Biomedical Research Dr, Pifarré Foundation (IRBLleida), Lleida, Spain.
5Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany. Stefanie.Schmitteckert@med.uni-heidelberg.de.
6University of Leeds, St. James's University Hospital, Leeds, UK.
7Mayo Clinic, Jacksonville, FL, USA.
8Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany.
9Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany.
10Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.
11Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
12Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Derio, Spain.
13IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
14nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
15Martin-Luther-Hospital, Berlin, Germany.
16Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany.
17University of Erlangen, Erlangen, Germany.
18Israelitisches Krankenhaus, Hamburg, Germany.
19Helios Klinik Krefeld, Krefeld, Germany.
20Krankenhaus Vilsbiburg, Vilsbiburg, Germany.
21German Cancer Research Center, Heidelberg, Germany.
22Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.
23APC Microbiome Ireland, University College Cork, Cork, Ireland.
24Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
25Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA.
26Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.
27Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile.
28Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA, USA.
29Washington University School of Medicine, St. Louis, MO, USA.
30Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
31Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
32CRG, Centre for Genomic Regulation, Barcelona, Spain.
33ISGlobal, Barcelona, Spain.
34Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain.
35Life and Brain Center, Bonn, Germany.
36Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
37Institute of Clinical Molecular Biology, Kiel, Germany.
38Institute of Epidemiology, Kiel, Germany.
39TARGID, University Hospital Leuven, Louvain, Belgium.
40Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
41Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany.
42Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain.
43Nestlé Institute of Health Sciences, Nestlé Research, Société Des Produits Nestlé S.A, Vers-chez-les-Blanc, Lausanne, Switzerland.
44Department of Psychosomatic Medicine, Division of Theragnostics, University Hospital Basel, Basel, Switzerland.
45Faculty of Medicine, University of Basel, Basel, Switzerland.
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.