Artículos de revistas
The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
Fecha
2021Registro en:
Journal of Cellular and Molecular Medicine (2021) 25:16 Pág. 8047 - 8061
10.1111/jcmm.16736
Autor
Mohr, Sandra
Fritz, Nikola
Hammer, Christian
Martínez, Cristina
Berens, Sabrina
Schmitteckert, Stefanie
Wahl, Verena
Schmidt, Malin
Houghton, Lesley A.
Goebel Stengel, Miriam
Kabisch, María
Götze, Dorothea
Milovač, Irina
D’Amato, Mauro
Zheng, Tenghao
Röth, Ralph
Mönnikes, Hubert
Engel, Felicitas
Gauss, Annika
Tesarz, Jonás
Raithel, Martin
Andresen, Viola
Frieling, Thomas
Keller, Jutta
Pehl, Christian
Stein Thöringer, Christoph
Clarke, Gerard
Kennedy, Paul J.
Cryan, John F.
Dinan, Timothy G.
Quigley, Eamonn M. M.
Spiller, Robin
Beltrán Muñoz, Caroll Jenny
Madrid Silva, Ana Maria
Torres, Verónica
Pérez De Arce Oñate, Edith Paola
Herzog, Wolfgang
Mayer, Emeran A.
Sayuk, Gregory
Gazouli, María
Karamanolis, George
Kapur Pojskič, Lejla
Bustamante, Mariona
Rabionet, Raquel
Estivil, Xavier
Franke, André
Lieb, Wolfgang
Boeckxstaens, Guy
Wouters, Mira M.
Simrén, Magnus
Rappold, Gudrun A.
Vicario, María
Santos, Javier
Schaefert, Rainer
Lorenzo Bermejo, Justo
Niesler, Beate
Institución
Resumen
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