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

被引：169

作者：

Kapeller, Johannes ^{[1
]}

Houghton, Lesley A. ^{[3
]}

Moennikes, Hubert ^{[4
]}

Walstab, Jutta ^{[5
]}

Moeller, Dorothee ^{[1
]}

Boenisch, Heinz ^{[5
]}

Burwinkel, Barbara ^{[6
]}

Autschbach, Frank ^{[7
]}

Funke, Benjamin ^{[7
]}

Lasitschka, Felix ^{[7
]}

Gassler, Nikolaus ^{[8
]}

Fischer, Christine ^{[2
]}

Whorwell, Peter J. ^{[3
]}

Atkinson, Wendy ^{[3
]}

Fell, Catherine ^{[3
]}

Buechner, Karl J. ^{[9
]}

Schmidtmann, Marco ^{[4
]}

van der Voort, Ivo ^{[9
]}

Wisser, Anna-Sophia ^{[4
]}

Berg, Thomas ^{[9
]}

Rappold, Gudrun ^{[1
]}

Niesler, Beate ^{[1
]}

机构：

[1] Univ Heidelberg, Dept Human Mol Genet, D-69120 Heidelberg, Germany

[2] Univ Heidelberg, Inst Human Genet, D-69120 Heidelberg, Germany

[3] Univ Manchester, Wythenshawe Hosp, Neurogastroenterol Unit, Manchester, Lancs, England

[4] Martin Luther Hosp, Inst Neurogastroenterol, Dept Med, Berlin, Germany

[5] Univ Bonn, Inst Pharmacol & Toxicol, D-53113 Bonn, Germany

[6] Helmholtz Univ, Deutsch Krebsforschungszentrum, German Canc Res Ctr, Grp Mol Epidemiol,Div Mol Genet Epidemiol, Heidelberg, Germany

[7] Univ Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany

[8] Rhein Westfal TH Aachen, Univ Hosp, Inst Pathol, D-52074 Aachen, Germany

[9] Univ Med Berlin, Charite, Dept Med, Div Hepatol Gastroenterol & Endocrinol, Berlin, Germany

来源：

HUMAN MOLECULAR GENETICS | 2008年 / 17卷 / 19期

关键词：

D O I：

10.1093/hmg/ddn195

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：2967 / 2977

页数：11

共 45 条

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