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The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome

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...

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Hauptverfasser: Mohr, Sandra (VerfasserIn) , Fritz, Nikola (VerfasserIn) , Hammer, Christian (VerfasserIn) , Martínez, Cristina (VerfasserIn) , Berens, Sabrina (VerfasserIn) , Mellein, Stefanie (VerfasserIn) , Wahl, Verena (VerfasserIn) , Schmidt, Malin (VerfasserIn) , Houghton, Lesley A. (VerfasserIn) , Goebel-Stengel, Miriam (VerfasserIn) , Kabisch, Maria (VerfasserIn) , Götze, Dorothea (VerfasserIn) , Milovač, Irina (VerfasserIn) , D’Amato, Mauro (VerfasserIn) , Zheng, Tenghao (VerfasserIn) , Röth, Ralph (VerfasserIn) , Mönnikes, Hubert (VerfasserIn) , Engel, Felicitas (VerfasserIn) , Gauss, Annika (VerfasserIn) , Tesarz, Jonas (VerfasserIn) , Raithel, Martin (VerfasserIn) , Andresen, Viola (VerfasserIn) , Frieling, Thomas (VerfasserIn) , Keller, Jutta (VerfasserIn) , Pehl, Christian (VerfasserIn) , Stein-Thöringer, Christoph (VerfasserIn) , Clarke, Gerard (VerfasserIn) , Kennedy, Paul J. (VerfasserIn) , Cryan, John F. (VerfasserIn) , Dinan, Timothy G. (VerfasserIn) , Quigley, Eamonn M. M. (VerfasserIn) , Spiller, Robin (VerfasserIn) , Beltrán, Caroll (VerfasserIn) , Madrid, Ana María (VerfasserIn) , Torres, Verónica (VerfasserIn) , Arce, Edith Pérez de (VerfasserIn) , Herzog, Wolfgang (VerfasserIn) , Mayer, Emeran A. (VerfasserIn) , Sayuk, Gregory (VerfasserIn) , Gazouli, Maria (VerfasserIn) , Karamanolis, George (VerfasserIn) , Kapur-Pojskič, Lejla (VerfasserIn) , Bustamante, Mariona (VerfasserIn) , Rabionet, Raquel (VerfasserIn) , Estivil, Xavier (VerfasserIn) , Franke, André (VerfasserIn) , Lieb, Wolfgang (VerfasserIn) , Boeckxstaens, Guy (VerfasserIn) , Wouters, Mira M. (VerfasserIn) , Simrén, Magnus (VerfasserIn) , Rappold, Gudrun A. (VerfasserIn) , Vicario, Maria (VerfasserIn) , Santos, Javier (VerfasserIn) , Schaefert, Rainer (VerfasserIn) , Lorenzo Bermejo, Justo (VerfasserIn) , Niesler, Beate (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: August 2021
In: Journal of cellular and molecular medicine
Year: 2021, Jahrgang: 25, Heft: 16, Pages: 8047-8061
ISSN:1582-4934
DOI:10.1111/jcmm.16736
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1111/jcmm.16736
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/jcmm.16736
Volltext
Verfasserangaben: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

MARC

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245 1 4 |a The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome  |c 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 
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520 |a 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. 
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SRT |a MOHRSANDRAALTERNATIV2021 

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