Human Molecular Genetics Advance Access originally published online on July 9, 2008
Human Molecular Genetics 2008 17(19):2967-2977; doi:10.1093/hmg/ddn195
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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
1 Department of Human Molecular Genetics 2 Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany 3 Neurogastroenterology Unit, University of Manchester, Wythenshawe Hospital, Manchester, UK 4 Department of Medicine, Institute of Neurogastroenterology at Martin-Luther Hospital, Berlin, Germany 5 Institute of Pharmacology and Toxicology, University of Bonn, Reuterstrasse 2b, 53113 Bonn, Germany 6 Division of Molecular Genetic Epidemiology, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany 7 Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany 8 Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany 9 Department of Medicine, Division of Hepatology, Gastroenterology, and Endocrinology, Charité, Campus Virchow, Universitätsmedizin Berlin, Berlin, Germany
* To whom correspondence should be addressed. Tel: +49 6221565058; Fax: +49 6221568884; Email: beate.niesler{at}med.uni-heidelberg.de
Received March 28, 2008; Revised June 25, 2008; Accepted July 4, 2008
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.
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