- Fecal Incontinence
|The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
J Cell Mol Med. 2021 Jun 24. doi: 10.1111/jcmm.16736. Online ahead of print.
Sandra Mohr 1, Nikola Fritz 1, Christian Hammer 2 3, Cristina Martínez 1 4 5, Sabrina Berens 6, Stefanie Schmitteckert 1, Verena Wahl 1, Malin Schmidt 1 7, Lesley A Houghton 8 9, Miriam Goebel-Stengel 10 11, Maria Kabisch 12, Dorothea Götze 1, Irina Milovac 13, Mauro D'Amato 14 15 16 17, Tenghao Zheng 14 15, Ralph Röth 1 18, Hubert Mönnikes 19, Felicitas Engel 6, Annika Gauss 20, Jonas Tesarz 6, Martin Raithel 21, Viola Andresen 22, Thomas Frieling 23, Jutta Keller 22, Christian Pehl 24, Christoph Stein-Thöringer 25, Gerard Clarke 26 27, Paul J Kennedy 26 27, John F Cryan 26 27 28, Timothy G Dinan 26 27, Eamonn M M Quigley 27 29, Robin Spiller 30, Caroll Beltrán 31, Ana María Madrid 31, Verónica Torres 31, Edith Pérez de Arce 31, Wolfgang Herzog 6, Emeran A Mayer 32, Gregory Sayuk 33, Maria Gazouli 34, George Karamanolis 35, Lejla Kapur-Pojskic 36, Mariona Bustamante 37 38, Raquel Rabionet 39, Xavier Estivil 37, André Franke 40, Wolfgang Lieb 41, Guy Boeckxstaens 42, Mira M Wouters 42, Magnus Simrén 43, Gudrun A Rappold 1 44, Maria Vicario 45, Javier Santos 45, Rainer Schaefert 46 47, Justo Lorenzo-Bermejo 12, Beate Niesler 1 18 44
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.