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

Author information

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.

Abstract

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.