Περίληψη:
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.
Συγγραφείς:
Mohr, Sandra
Fritz, Nikola
Hammer, Christian
Martinez,
Cristina
Berens, Sabrina
Schmitteckert, Stefanie
Wahl,
Verena
Schmidt, Malin
Houghton, Lesley A.
Goebel-Stengel,
Miriam
Kabisch, Maria
Gotze, Dorothea
Milovac, Irina and
D'Amato, Mauro
Zheng, Tenghao
Roth, Ralph
Monnikes, Hubert
and Engel, Felicitas
Gauss, Annika
Tesarz, Jonas
Raithel,
Martin
Andresen, Viola
Frieling, Thomas
Keller, Jutta and
Pehl, Christian
Stein-Thoringer, Christoph
Clarke, Gerard and
Kennedy, Paul J.
Cryan, John F.
Dinan, Timothy G.
Quigley,
Eamonn M. M.
Spiller, Robin
Beltran, Caroll
Madrid, Ana
Maria
Torres, Veronica
Perez de Arce, Edith
Herzog, Wolfgang
and Mayer, Emeran A.
Sayuk, Gregory
Gazouli, Maria and
Karamanolis, George
Kapur-Pojskic, Lejla
Bustamante, Mariona and
Rabionet, Raquel
Estivil, Xavier
Franke, Andre
Lieb,
Wolfgang
Boeckxstaens, Guy
Wouters, Mira M.
Simren, Magnus
and Rappold, Gudrun A.
Vicario, Maria
Santos, Javier and
Schaefert, Rainer
Lorenzo-Bermejo, Justo
Niesler, Beate
