The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.
5-HT
IBS
IBS-C
serotonin transporter
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
24
05
2021
received:
01
11
2020
accepted:
26
05
2021
pubmed:
25
6
2021
medline:
19
2
2022
entrez:
24
6
2021
Statut:
ppublish
Résumé
Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
Identifiants
pubmed: 34165249
doi: 10.1111/jcmm.16736
pmc: PMC8358858
doi:
Substances chimiques
Biomarkers
0
SLC6A4 protein, human
0
Serotonin Plasma Membrane Transport Proteins
0
Serotonin
333DO1RDJY
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8047-8061Subventions
Organisme : Science Foundation Ireland
ID : SFI/12/RC/2273 P2
Pays : Ireland
Organisme : Health Research Board
ID : POR/2011/23
Pays : Ireland
Informations de copyright
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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