The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
Por:
Mohr S, Fritz N, Hammer C, Martínez C, Berens S, Schmitteckert S, Wahl V, Schmidt M, Houghton LA, Goebel-Stengel M, Kabisch M, Götze D, Milovac I, D'Amato M, Zheng T, Röth R, Mönnikes H, Engel F, Gauss A, Tesarz J, Raithel M, Andresen V, Frieling T, Keller J, Pehl C, Stein-Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Pérez de Arce E, Herzog W, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Kapur-Pojskic L, Bustamante M, Rabionet-Janssen R, Estivil X, Franke A, Lieb W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo-Bermejo J and Niesler B
Publicada:
1 ago 2021
Ahead of Print:
1 jun 2021
Resumen:
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.
Filiaciones:
Mohr S:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Fritz N:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Hammer C:
Department of Cancer Immunology, Genentech, South San Francisco, CA, USA
Department of Human Genetics, Genentech, South San Francisco, CA, USA
Martínez C:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
Lleida Institute for Biomedical Research, Dr. Pifarré Foundation (IRBLleida), Lleida, Spain
Berens S:
Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
Schmitteckert S:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Wahl V:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Schmidt M:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Department of Translational Brain Research, Central Institute of Mental Health
Houghton LA:
St. James's University Hospital, University of Leeds, Leeds, UK
Mayo Clinic, Jacksonville, FL, USA
Goebel-Stengel M:
Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany
Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
Kabisch M:
Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
Götze D:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Milovac I:
Faculty of Medicine, University Banja Luka, Banja Luka, Bosnia and Herzegovina
D'Amato M:
School of Biological Sciences, Monash University, Clayton, VIC, Australia
Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastián, Spain
Ikerbasque, Basque Foundation for Science, Bilbao, Spain
Zheng T:
School of Biological Sciences, Monash University, Clayton, VIC, Australia
Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Röth R:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
Mönnikes H:
Martin-Luther-Hospital, Berlin, Germany
Engel F:
Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
Gauss A:
Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany
Tesarz J:
Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
Raithel M:
University of Erlangen, Erlangen, Germany
Andresen V:
Israelitisches Krankenhaus, Hamburg, Germany
Frieling T:
Helios Klinik Krefeld, Krefeld, Germany
Keller J:
Israelitisches Krankenhaus, Hamburg, Germany
Pehl C:
Krankenhaus Vilsbiburg, Vilsbiburg, Germany
Stein-Thöringer C:
German Cancer Research Center, Heidelberg, Germany
Clarke G:
Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland
APC Microbiome Ireland, University College Cork, Cork, Ireland
Kennedy PJ:
Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland
APC Microbiome Ireland, University College Cork, Cork, Ireland
Cryan JF:
Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland
APC Microbiome Ireland, University College Cork, Cork, Ireland
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Dinan TG:
Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland
APC Microbiome Ireland, University College Cork, Cork, Ireland
Quigley EMM:
APC Microbiome Ireland, University College Cork, Cork, Ireland
Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA
Spiller R:
Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
Beltrán C:
Gastroenterology Unit, Hospital Clínico Universidad de Chile, Medicine Department, Universidad de Chile, Santiago de Chile, Chile
Madrid AM:
Gastroenterology Unit, Hospital Clínico Universidad de Chile, Medicine Department, Universidad de Chile, Santiago de Chile, Chile
Torres V:
Gastroenterology Unit, Hospital Clínico Universidad de Chile, Medicine Department, Universidad de Chile, Santiago de Chile, Chile
Pérez de Arce E:
Gastroenterology Unit, Hospital Clínico Universidad de Chile, Medicine Department, Universidad de Chile, Santiago de Chile, Chile
Herzog W:
Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
Mayer EA:
Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA, USA
Sayuk G:
Washington University School of Medicine, St. Louis, MO, USA
Gazouli M:
Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Karamanolis G:
Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, "Laikon" General Hospital, Athens, Greece
Kapur-Pojskic L:
Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Bustamante M:
CRG, Centre for Genomic Regulation, Barcelona, Spain
ISGlobal, Barcelona, Spain
Rabionet-Janssen R:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, CIBERER, IRSJD, Universitat de Barcelona, Barcelona, Spain
Estivil X:
CRG, Centre for Genomic Regulation, Barcelona, Spain
Franke A:
Institute of Clinical Molecular Biology, Kiel, Germany
Lieb W:
Institute of Epidemiology, Kiel, Germany
Boeckxstaens G:
TARGID, University Hospital Leuven, Leuven, Belgium
Wouters MM:
TARGID, University Hospital Leuven, Leuven, Belgium
Simrén M:
Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
Rappold GA:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
Vicario M:
Institut de Recerca Vall d'Hebron, Hospital Vall d'Hebron, Barcelona, Spain
Santos J:
Institut de Recerca Vall d'Hebron, Hospital Vall d'Hebron, Barcelona, Spain
Schaefert R:
Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
Faculty of Medicine, University of Basel, Basel, Switzerland
Lorenzo-Bermejo J:
Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
Niesler B:
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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