TY - JOUR
TI - The alternative serotonin transporter promoter P2 impacts gene function
in females with irritable bowel syndrome
AU - Mohr, Sandra
AU - Fritz, Nikola
AU - Hammer, Christian
AU - Martinez,
AU - Cristina
AU - Berens, Sabrina
AU - Schmitteckert, Stefanie
AU - Wahl,
AU - Verena
AU - Schmidt, Malin
AU - Houghton, Lesley A.
AU - Goebel-Stengel,
AU - Miriam
AU - Kabisch, Maria
AU - Gotze, Dorothea
AU - Milovac, Irina and
AU - D'Amato, Mauro
AU - Zheng, Tenghao
AU - Roth, Ralph
AU - Monnikes, Hubert
AU - and Engel, Felicitas
AU - Gauss, Annika
AU - Tesarz, Jonas
AU - Raithel,
AU - Martin
AU - Andresen, Viola
AU - Frieling, Thomas
AU - Keller, Jutta and
AU - Pehl, Christian
AU - Stein-Thoringer, Christoph
AU - Clarke, Gerard and
AU - Kennedy, Paul J.
AU - Cryan, John F.
AU - Dinan, Timothy G.
AU - Quigley,
AU - Eamonn M. M.
AU - Spiller, Robin
AU - Beltran, Caroll
AU - Madrid, Ana
AU - Maria
AU - Torres, Veronica
AU - Perez de Arce, Edith
AU - Herzog, Wolfgang
AU - and Mayer, Emeran A.
AU - Sayuk, Gregory
AU - Gazouli, Maria and
AU - Karamanolis, George
AU - Kapur-Pojskic, Lejla
AU - Bustamante, Mariona and
AU - Rabionet, Raquel
AU - Estivil, Xavier
AU - Franke, Andre
AU - Lieb,
AU - Wolfgang
AU - Boeckxstaens, Guy
AU - Wouters, Mira M.
AU - Simren, Magnus
AU - and Rappold, Gudrun A.
AU - Vicario, Maria
AU - Santos, Javier and
AU - Schaefert, Rainer
AU - Lorenzo-Bermejo, Justo
AU - Niesler, Beate
JO - Journal of Cellular and Molecular Medicine
PY - 2021
VL - 25
TODO - 16
SP - 8047-8061
PB - Wiley
SN - 1582-1838, 1582-4934
TODO - 10.1111/jcmm.16736
TODO - 5-HT; IBS; IBS-C; serotonin transporter
TODO - 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.
ER -