Journal Article

First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome

Johannes Kapeller, Lesley A. Houghton, Hubert Mönnikes, Jutta Walstab, Dorothee Möller, Heinz Bönisch, Barbara Burwinkel, Frank Autschbach, Benjamin Funke, Felix Lasitschka, Nikolaus Gassler, Christine Fischer, Peter J. Whorwell, Wendy Atkinson, Catherine Fell, Karl J. Büchner, Marco Schmidtmann, Ivo van der Voort, Anna-Sophia Wisser, Thomas Berg, Gudrun Rappold and Beate Niesler

in Human Molecular Genetics

Volume 17, issue 19, pages 2967-2977
Published in print October 2008 | ISSN: 0964-6906
Published online July 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn195
First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome

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Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3′-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3′-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT–PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.

Journal Article.  6937 words.  Illustrated.

Subjects: Genetics and Genomics

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