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.
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.
Kapeller
Johannes
J
Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Houghton
Lesley A
LA
Mönnikes
Hubert
H
Walstab
Jutta
J
Möller
Dorothee
D
Bönisch
Heinz
H
Burwinkel
Barbara
B
Autschbach
Frank
F
Funke
Benjamin
B
Lasitschka
Felix
F
Gassler
Nikolaus
N
Fischer
Christine
C
Whorwell
Peter J
PJ
Atkinson
Wendy
W
Fell
Catherine
C
Büchner
Karl J
KJ
Schmidtmann
Marco
M
van der Voort
Ivo
I
Wisser
Anna-Sophia
AS
Berg
Thomas
T
Rappold
Gudrun
G
Niesler
Beate
B
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
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