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

Hum Mol Genet. 2008 Oct 1;17(19):2967-77. doi: 10.1093/hmg/ddn195. Epub 2008 Jul 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adolescent
  • Adult
  • Aged
  • Case-Control Studies
  • Cell Line
  • Cohort Studies
  • Diarrhea / genetics*
  • Diarrhea / metabolism
  • Female
  • Gene Expression
  • Germany
  • Humans
  • Intestinal Mucosa
  • Irritable Bowel Syndrome / genetics*
  • Irritable Bowel Syndrome / metabolism
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Mutation
  • Receptors, Serotonin / genetics*
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT3
  • Species Specificity
  • United Kingdom


  • 3' Untranslated Regions
  • HTR3A protein, human
  • HTR3E protein, human
  • MIRN510 microRNA, human
  • MicroRNAs
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3