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

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; Robin Spiller; 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

doi:10.1007/s00109-022-02244-w

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

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 KellerThomas Frieling, 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, 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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1617-1627
Number of pages	11
Journal	Journal of Molecular Medicine
Volume	100
Issue number	11
DOIs	https://doi.org/10.1007/s00109-022-02244-w
State	Published - Nov 2022

Keywords

Females
IBS-D
Irritable bowel syndrome
Serotonin type 3 receptor

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery
Genetics(clinical)

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10.1007/s00109-022-02244-w

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Fritz, N., Berens, S., Dong, Y., Martínez, C., Schmitteckert, S., Houghton, L. A., Goebel-Stengel, M., Wahl, V., Kabisch, M., Götze, D., D’Amato, M., Zheng, T., Röth, R., Mönnikes, H., Tesarz, J., Engel, F., Gauss, A., Raithel, M., Andresen, V., ... Niesler, B. (2022). The serotonin receptor 3E variant is a risk factor for female IBS-D. Journal of Molecular Medicine, 100(11), 1617-1627. https://doi.org/10.1007/s00109-022-02244-w

Fritz, N, Berens, S, Dong, Y, Martínez, C, Schmitteckert, S, Houghton, LA, Goebel-Stengel, M, Wahl, V, Kabisch, M, Götze, D, D’Amato, M, Zheng, T, Röth, R, Mönnikes, H, Tesarz, J, Engel, F, Gauss, A, Raithel, M, Andresen, V, Keller, J, Frieling, T, Pehl, C, Stein-Thöringer, C, Clarke, G, Kennedy, PJ, Cryan, JF, Dinan, TG, Quigley, EMM, Spiller, R, Beltrán, C, Madrid, AM, Torres, V, Mayer, EA, Sayuk, G, Gazouli, M, Karamanolis, G, Bustamante, M, Estivil, X, Rabionet, R, Hoffmann, P, Nöthen, MM, Heilmann-Heimbach, S, Schmidt, B, Franke, A, Lieb, W, Herzog, W, Boeckxstaens, G, Wouters, MM, Simrén, M, Rappold, GA, Vicario, M, Santos, J, Schaefert, R, Lorenzo-Bermejo, J & Niesler, B 2022, 'The serotonin receptor 3E variant is a risk factor for female IBS-D', Journal of Molecular Medicine, vol. 100, no. 11, pp. 1617-1627. https://doi.org/10.1007/s00109-022-02244-w

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title = "The serotonin receptor 3E variant is a risk factor for female IBS-D",

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.",

keywords = "Females, IBS-D, Irritable bowel syndrome, Serotonin type 3 receptor",

author = "Nikola Fritz and Sabrina Berens and Yuanjun Dong and Cristina Mart{\'i}nez and Stefanie Schmitteckert and Houghton, {Lesley A.} and Miriam Goebel-Stengel and Verena Wahl and Maria Kabisch and Dorothea G{\"o}tze and Mauro D{\textquoteright}Amato and Tenghao Zheng and Ralph R{\"o}th and Hubert M{\"o}nnikes and Jonas Tesarz and Felicitas Engel and Annika Gauss and Martin Raithel and Viola Andresen and Jutta Keller and Thomas Frieling and Christian Pehl and Christoph Stein-Th{\"o}ringer and Gerard Clarke and Kennedy, {Paul J.} and Cryan, {John F.} and Dinan, {Timothy G.} and Quigley, {Eamonn M.M.} and Robin Spiller and Caroll Beltr{\'a}n and Madrid, {Ana Mar{\'i}a} and Ver{\'o}nica Torres and Mayer, {Emeran A.} and Gregory Sayuk and Maria Gazouli and George Karamanolis and Mariona Bustamante and Xavier Estivil and Raquel Rabionet and Per Hoffmann and N{\"o}then, {Markus M.} and Stefanie Heilmann-Heimbach and B{\"o}rge Schmidt and Andr{\'e} Franke and Wolfgang Lieb and Wolfgang Herzog and Guy Boeckxstaens and Wouters, {Mira M.} and Magnus Simr{\'e}n and Rappold, {Gudrun A.} and Maria Vicario and Javier Santos and Rainer Schaefert and Justo Lorenzo-Bermejo and Beate Niesler",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

doi = "10.1007/s00109-022-02244-w",

language = "English (US)",

volume = "100",

pages = "1617--1627",

journal = "Journal of Molecular Medicine",

issn = "0946-2716",

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TY - JOUR

T1 - The serotonin receptor 3E variant is a risk factor for female IBS-D

AU - Fritz, Nikola

AU - Berens, Sabrina

AU - Dong, Yuanjun

AU - Martínez, Cristina

AU - Schmitteckert, Stefanie

AU - Houghton, Lesley A.

AU - Goebel-Stengel, Miriam

AU - Wahl, Verena

AU - Kabisch, Maria

AU - Götze, Dorothea

AU - D’Amato, Mauro

AU - Zheng, Tenghao

AU - Röth, Ralph

AU - Mönnikes, Hubert

AU - Tesarz, Jonas

AU - Engel, Felicitas

AU - Gauss, Annika

AU - Raithel, Martin

AU - Andresen, Viola

AU - Keller, Jutta

AU - Frieling, Thomas

AU - Pehl, Christian

AU - Stein-Thöringer, Christoph

AU - Clarke, Gerard

AU - Kennedy, Paul J.

AU - Cryan, John F.

AU - Dinan, Timothy G.

AU - Quigley, Eamonn M.M.

AU - Spiller, Robin

AU - Beltrán, Caroll

AU - Madrid, Ana María

AU - Torres, Verónica

AU - Mayer, Emeran A.

AU - Sayuk, Gregory

AU - Gazouli, Maria

AU - Karamanolis, George

AU - Bustamante, Mariona

AU - Estivil, Xavier

AU - Rabionet, Raquel

AU - Hoffmann, Per

AU - Nöthen, Markus M.

AU - Heilmann-Heimbach, Stefanie

AU - Schmidt, Börge

AU - Franke, André

AU - Lieb, Wolfgang

AU - Herzog, Wolfgang

AU - Boeckxstaens, Guy

AU - Wouters, Mira M.

AU - Simrén, Magnus

AU - Rappold, Gudrun A.

AU - Vicario, Maria

AU - Santos, Javier

AU - Schaefert, Rainer

AU - Lorenzo-Bermejo, Justo

AU - Niesler, Beate

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

KW - Females

KW - IBS-D

KW - Irritable bowel syndrome

KW - Serotonin type 3 receptor

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

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