@article{3029490,
    title = "The alternative serotonin transporter promoter P2 impacts gene function
in females with irritable bowel syndrome",
    author = "Mohr, Sandra and Fritz, Nikola and Hammer, Christian and Martinez, and Cristina and Berens, Sabrina and Schmitteckert, Stefanie and Wahl, and Verena and Schmidt, Malin and Houghton, Lesley A. and Goebel-Stengel, and Miriam and Kabisch, Maria and Gotze, Dorothea and Milovac, Irina and and D'Amato, Mauro and Zheng, Tenghao and Roth, Ralph and Monnikes, Hubert and and Engel, Felicitas and Gauss, Annika and Tesarz, Jonas and Raithel, and Martin and Andresen, Viola and Frieling, Thomas and Keller, Jutta and and Pehl, Christian and Stein-Thoringer, Christoph and Clarke, Gerard and and Kennedy, Paul J. and Cryan, John F. and Dinan, Timothy G. and Quigley, and Eamonn M. M. and Spiller, Robin and Beltran, Caroll and Madrid, Ana and Maria and Torres, Veronica and Perez de Arce, Edith and Herzog, Wolfgang and and Mayer, Emeran A. and Sayuk, Gregory and Gazouli, Maria and and Karamanolis, George and Kapur-Pojskic, Lejla and Bustamante, Mariona and and Rabionet, Raquel and Estivil, Xavier and Franke, Andre and Lieb, and Wolfgang and Boeckxstaens, Guy and Wouters, Mira M. and Simren, Magnus and and Rappold, Gudrun A. and Vicario, Maria and Santos, Javier and and Schaefert, Rainer and Lorenzo-Bermejo, Justo and Niesler, Beate",
    journal = "Journal of Cellular and Molecular Medicine",
    year = "2021",
    volume = "25",
    number = "16",
    pages = "8047-8061",
    publisher = "Wiley",
    issn = "1582-1838, 1582-4934",
    doi = "10.1111/jcmm.16736",
    keywords = "5-HT; IBS; IBS-C; serotonin transporter",
    abstract = "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."
}