The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
Year: 2021
Type: article
Study design: Observational Study
Abstract: Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
DOI: 10.1111/jcmm.16736
Authors: Sandra Mohr, Nikola Fritz, Christian Hammer, Cristina Martínez, Sabrina Berens, Stefanie Schmitteckert, Verena Wahl, Malin Schmidt, Lesley A. Houghton, Miriam Goebel‐Stengel, Maria Kabisch, Dorothea Götze, Irina Milovač, Mauro D’Amato, Tenghao Zheng, Ralph Röth, Hubert Mönnikes, Felicitas Engel, Annika Gauss, Jonas Tesarz, Martin Raithel, Viola Andresen, Thomas Frieling, Jutta Keller, Christian Pehl, Christoph Stein‐Thöringer, Gerard Clarke, Paul J. Kennedy, John F. Cryan, Timothy G. Dinan, Eamonn M. M. Quigley, Robin Spiller, Caroll Beltrán, Ana María Madrid, Verónica Torres, Edith Pérez de Arce, Wolfgang Herzog, Emeran A. Mayer, Gregory Sayuk, Maria Gazouli, George Karamanolis, Lejla Kapur‐Pojskič, Mariona Bustamante, Raquel Rabionet, Xavier Estivil, André Franke, Wolfgang Lieb, Guy Boeckxstaens, Mira M. Wouters, Magnus Simrén, Gudrun A. Rappold, Maria Vicario, Javier Santos, Rainer Schaefert, Justo Lorenzo‐Bermejo, Beate Niesler
Institutions: Heidelberg University, University Hospital Heidelberg, Genentech, Instituto de Investigación Biomédica de Lleida, Central Institute of Mental Health, University of Leeds, Mayo Clinic, St James's University Hospital, Mayo Clinic in Florida, Universitätsklinikum Tübingen, Helios Kliniken, University of Banja Luka, Ikerbasque, Karolinska Institutet, Biogipuzkoa Health Research Institute, Monash University, Martin-Luther-Krankenhaus, Friedrich-Alexander-Universität Erlangen-Nürnberg, Israelitisches Krankenhaus, Helios Klinikum Krefeld, Hôpital Kirchberg, German Cancer Research Center, University College Cork, APC Microbiome Institute, Houston Methodist, University of Nottingham, NIHR Nottingham Digestive Diseases Biomedical Research Unit, Hospital Clínico de la Universidad de Chile, University of Chile, University of California, Los Angeles, Washington University in St. Louis, National and Kapodistrian University of Athens, Laiko General Hospital of Athens, University of Sarajevo, Centre for Genomic Regulation, Barcelona Institute for Global Health, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Joan de Déu, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Christian-Albrechts-Universität zu Kiel, University of Gothenburg, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, University of Basel, University Hospital of Basel
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,388
Awards: G1383882326, Mecanismos neuroinmunológicos de activación de la respuesta inmunitaria humoral en el Sindrome del Intestino Irritable: base orgánica de la disfunción intestinal, G2377181310, G2998604935, Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine, Desarrollo de un panel diagnóstico innovador para el Síndrome del Intestino irritable basado en la expresión sistémica diferencial de miRNAs, asociado a las manifestaciones clínicas y a la patología intestinal subyacente, G3559709381, G448368138, G5098725405, APC_Phase 2, G528836942, G5594568950
OpenAlex ID: W3174449504