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Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. Ascis-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 genesHTR3AandHTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novelHTR3E3′-UTR variant c.*76G&gt;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&gt;A with female IBS-D (P= 0.0002, OR = 5.39). In a reporter assay, c.*76G&gt;A affected binding of miR-510 to theHTR3E3′-UTR and caused elevated luciferase expression.HTR3Eand miR-510 co-localize in enterocytes of the gut epithelium as shown byin situhybridization and RT–PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with acis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.

human molecular genetics

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