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Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT<jats:sub>3<\/jats:sub> receptor family. 5-HT<jats:sub>3<\/jats:sub>Rs are encoded by <jats:italic>HTR3<\/jats:italic> genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT<jats:sub>3<\/jats:sub>R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in <jats:italic>HTR3A<\/jats:italic> c.-42C\u2009&gt;\u2009T (rs1062613), <jats:italic>HTR3C<\/jats:italic> p.N163K (rs6766410), and <jats:italic>HTR3E<\/jats:italic> c.*76G\u2009&gt;\u2009A (rs56109847\u2009=\u2009rs62625044) being associated with IBS-D, and the <jats:italic>HTR3B<\/jats:italic> 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 <jats:italic>HTR3<\/jats:italic> 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 <jats:italic>HTR3E<\/jats:italic> c.*76G\u2009&gt;\u2009A (rs56109847\u2009=\u2009rs62625044) to be associated with female IBS-D (OR\u2009=\u20091.58; 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 <jats:italic>HTR3E<\/jats:italic> to be robustly expressed. On top, <jats:italic>HTR3E<\/jats:italic> transcript levels were significantly reduced in the sigma of IBS patients (<jats:italic>p<\/jats:italic>\u2009=\u20090.0187); more specifically, in those diagnosed with IBS-D (<jats:italic>p<\/jats:italic>\u2009=\u20090.0145). In conclusion, meta-analysis confirmed rs56109847\u2009=\u2009rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced <jats:italic>HTR3E<\/jats:italic> levels in the sigmoid colon of IBS-D patients, which underlines the relevance of <jats:italic>HTR3E<\/jats:italic> in the pathogenesis of IBS-D.\n<\/jats:p>","DOI":"10.1007\/s00109-022-02244-w","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T11:02:58Z","timestamp":1663585378000},"page":"1617-1627","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The serotonin receptor 3E variant is a risk factor for female IBS-D"],"prefix":"10.1007","volume":"100","author":[{"given":"Nikola","family":"Fritz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Berens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjun","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Schmitteckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley A.","family":"Houghton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Goebel-Stengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Wahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kabisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"G\u00f6tze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"D\u2019Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenghao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"R\u00f6th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"M\u00f6nnikes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Tesarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicitas","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Gauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Raithel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Andresen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Frieling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Pehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Stein-Th\u00f6ringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Cryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy G.","family":"Dinan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn M. 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Furthermore, a cohort of IBS patients and controls from the UK, USA, and Canada were included in this study; these were kindly provided by Glaxo Smith Kline (UK, GenIBS\/2005\/0000\/01).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent was obtained from all subjects.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate and consent for publication"}},{"value":"The authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}