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The serotonin receptor 3E variant is a risk factor for female IBS-D

Fritz, Nikola; Berens, Sabrina; Dong, Yuanjun; Martínez, Cristina; Schmitteckert, Stefanie; Houghton, Lesley A; Goebel-Stengel, Miriam; Wahl, Verena; Kabisch, Maria; Götze, Dorothea; D'Amato, Mauro; Zheng, Tenghao; Röth, Ralph; Mönnikes, Hubert; Tesarz, Jonas; Engel, Felicitas; Gauss, Annika; Raithel, Martin; Andresen, Viola; Keller, Jutta; Frieling, Thomas; Pehl, Christian; Stein-Thöringer, Christoph; Clarke, Gerard; Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Quigley, Eamonn M M; Spiller, Robin; Beltrán, Caroll; Madrid, Ana María; Torres, Verónica; Mayer, Emeran A; Sayuk, Gregory; Gazouli, Maria; Karamanolis, George; Bustamante, Mariona; Estivil, Xavier; Rabionet, Raquel; Hoffmann, Per; Nöthen, Markus M; Heilmann-Heimbach, Stefanie; Schmidt, Börge; Franke, André; Lieb, Wolfgang; Herzog, Wolfgang; Boeckxstaens, Guy; Wouters, Mira M; Simrén, Magnus; Rappold, Gudrun A; Vicario, Maria; Santos, Javier; Schaefert, Rainer; Lorenzo-Bermejo, Justo; Niesler, Beate

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Nikola Fritz

Sabrina Berens

Yuanjun Dong

Cristina Martínez

Stefanie Schmitteckert

Lesley A Houghton

Miriam Goebel-Stengel

Verena Wahl

Maria Kabisch

Dorothea Götze

Mauro D'Amato

Tenghao Zheng

Ralph Röth

Hubert Mönnikes

Jonas Tesarz

Felicitas Engel

Annika Gauss

Martin Raithel

Viola Andresen

Jutta Keller

Thomas Frieling

Christian Pehl

Christoph Stein-Thöringer

Gerard Clarke

Paul J Kennedy

John F Cryan

Timothy G Dinan

Eamonn M M Quigley

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Professor of Gastroenterology

Caroll Beltrán

Ana María Madrid

Verónica Torres

Emeran A Mayer

Gregory Sayuk

Maria Gazouli

George Karamanolis

Mariona Bustamante

Xavier Estivil

Raquel Rabionet

Per Hoffmann

Markus M Nöthen

Stefanie Heilmann-Heimbach

Börge Schmidt

André Franke

Wolfgang Lieb

Wolfgang Herzog

Guy Boeckxstaens

Mira M Wouters

Magnus Simrén

Gudrun A Rappold

Maria Vicario

Javier Santos

Rainer Schaefert

Justo Lorenzo-Bermejo

Beate Niesler


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.


Fritz, N., Berens, S., Dong, Y., Martínez, C., Schmitteckert, S., Houghton, L. A., …Niesler, B. (2022). The serotonin receptor 3E variant is a risk factor for female IBS-D. Journal of Molecular Medicine, 100, 1617–1627.

Journal Article Type Article
Acceptance Date Aug 4, 2022
Online Publication Date Sep 19, 2022
Publication Date Nov 1, 2022
Deposit Date Oct 21, 2022
Publicly Available Date Oct 24, 2022
Journal Journal of Molecular Medicine
Print ISSN 0946-2716
Electronic ISSN 1432-1440
Peer Reviewed Peer Reviewed
Volume 100
Pages 1617–1627
Keywords Irritable bowel syndrome, Females, Serotonin type 3 receptor, IBS-D
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