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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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: The serotonin receptor 3E variant is a risk factor for female IBS-D
  • Beteiligte: 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; [...]
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Journal of Molecular Medicine
  • Sprache: Englisch
  • DOI: 10.1007/s00109-022-02244-w
  • ISSN: 0946-2716; 1432-1440
  • Schlagwörter: Genetics (clinical) ; Drug Discovery ; Molecular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. 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 &gt; T (rs1062613), <jats:italic>HTR3C</jats:italic> p.N163K (rs6766410), and <jats:italic>HTR3E</jats:italic> c.*76G &gt; A (rs56109847 = rs62625044) 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 &gt; 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 <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> = 0.0187); more specifically, in those diagnosed with IBS-D (<jats:italic>p</jats:italic> = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 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. </jats:p>