title: 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.
abstract: 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.
authors.affiliation: Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kapeller
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Houghton
authors.forename: Hubert
authors.initials: H
authors.lastname: Mönnikes
authors.forename: Jutta
authors.initials: J
authors.lastname: Walstab
authors.forename: Dorothee
authors.initials: D
authors.lastname: Möller
authors.forename: Heinz
authors.initials: H
authors.lastname: Bönisch
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Frank
authors.initials: F
authors.lastname: Autschbach
authors.forename: Benjamin
authors.initials: B
authors.lastname: Funke
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Whorwell
authors.forename: Wendy
authors.initials: W
authors.lastname: Atkinson
authors.forename: Catherine
authors.initials: C
authors.lastname: Fell
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Büchner
authors.forename: Marco
authors.initials: M
authors.lastname: Schmidtmann
authors.forename: Ivo
authors.initials: I
authors.lastname: van der Voort
authors.forename: Anna-Sophia
authors.initials: AS
authors.lastname: Wisser
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.forename: Beate
authors.initials: B
authors.lastname: Niesler
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002460:Cell Line; D015331:Cohort Studies; D003967:Diarrhea / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005858:Germany; D006801:Humans; D007413:Intestinal Mucosa; D043183:Irritable Bowel Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D013045:Species Specificity; D006113:United Kingdom
chemical_list: D020413:3' Untranslated Regions; C509409:HTR3A protein, human; C476055:HTR3E protein, human; C532745:MIRN510 microRNA, human; D035683:MicroRNAs; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3