Citations 2
The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
Mohr, Sandra , Fritz, Nikola, Hammer, Christian , Martínez, Cristina , Berens, Sabrina , Schmitteckert, Stefanie , Wahl, Verena, Schmidt, Målin , Houghton, Lesley A. , Goebel‐Stengel, Miriam , Kabisch, Maria, Götze, Dorothea, Milovač, Irina , D’Amato, Mauro , Röth, Ralph , Mönnikes, Hubert, Engel, Felicitas , Gauss, Annika , Tesarz, Jonas , Raithel, Martin , Andresen, Viola , Frieling, Thomas , Pehl, Christian, Stein‐Thöringer, Christoph, Clarke, Gerard , Kennedy, Paul J. , Cryan, John F. , Spiller, Robert E. , Beltrán, Caroll J. , Madrid, Ana María , Torres, Verónica , Arce, Edith Pérez de , Herzog, Wolfgang , Sayuk, Gregory S. , Karamanolis, George, Pojskić, Lejla , Bustamante, Mariona , Rabionet, Raquel , Estivil, Xavier, Wouters, Mira M. , Rappold, Gudrun , Santos, Javier , Schaefert, Rainer , Niesler, Beate , Zheng, Tenghao , Engel, Felicitas , Gauss, Annika , Tesarz, Jonas , Raithel, Martin , Andresen, Viola , Frieling, Thomas , Keller, Jutta , Stein-Thöringer, Christoph , Clarke, Gerard , Kennedy, Paul J , Cryan, John F , Dinan, Timothy G , Quigley, Eamonn M M , Spiller, Robin , Madrid, Ana María , Pérez de Arce, Edith , Herzog, Wolfgang , Mayer, Emeran A , Sayuk, Gregory , Gazouli, Maria , 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, Maria , Santos, Javier , Schaefert, Rainer , Lorenzo-Bermejo, Justo , Niesler, Beate , D'Amato, Mauro , Houghton, L A , Martínez, Cristina , Zheng, Tenghao , Stein-Thöringer, Christoph K., Quigley, Eamonn M.M. , Torres, Verónica, Boeckxstaens, Guy E. , Simrén, Magnus , Bermejo, Justo Lorenzo
Journal of Cellular and Molecular Medicine | June 24, 2021 | Volume: 25 | Issue: 16 | Pages: 8047-8061
AbstractIrritable 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.
A meta‐analysis of immunogenetic Case–Control Association Studies in irritable bowel syndrome
Schmitteckert, Stefanie , Houghton, Lesley A. , Sayuk, Gregory S. , Camilleri, Michael , Olivo‐Díaz, Angélica , Spiller, Robert E. , Wouters, Mira M. , Bermejo, J Lorenzo, Niesler, Beate , Czogalla, Bastian , Boeckxstaens, Guy E. , Houghton, L A , Spiller, Robin
Neurogastroenterology & Motility | April 1, 2015 | Volume: 27 | Issue: 5 | Pages: 717-727
AbstractBackgroundTo date, genetic‐association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune‐related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk.MethodsWe conducted two independent case–control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta‐analysis which included 12 additional, earlier studies. The meta‐analysis comprised a total of 2894 patients (839 IBS‐C, 1073 IBS‐D, 502 IBS‐M), and 3138 healthy volunteers with self‐reported Caucasian ancestry.Key ResultsThe association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta‐analysis: IBS (OR 1.19, 95% CI 1.08–1.31), and IBS‐C (OR 1.24, 95% CI 1.08–1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes.Conclusions & InferencesOur meta‐analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS‐C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.