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Irritable Bowel Syndrome: HELP
Articles by Beate Niesler
Based on 12 articles published since 2008
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Between 2008 and 2019, B. Niesler wrote the following 12 articles about Irritable Bowel Syndrome.
 
+ Citations + Abstracts
1 Review Phenotyping of subjects for large scale studies on patients with IBS. 2016

Boeckxstaens, G E / Drug, V / Dumitrascu, D / Farmer, A D / Hammer, J / Hausken, T / Niesler, B / Pohl, D / Pojskic, L / Polster, A / Simren, M / Goebel-Stengel, M / Van Oudenhove, L / Vassallo, M / Wensaas, K-A / Aziz, Q / Houghton, L A / Anonymous3490872. ·Translational Research Center for Gastrointestinal Disorders, KULeuven & Department of Gastroenterology and Hepatology, University Hospital Leuven, Leuven, Belgium. · Gastroenterology Department, University Hospital "St Spiridon", Gr. T.Popa University of Medicine and Pharmacy, Iasi, Romania. · 2nd Medical Dept., Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. · Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, London, UK. · Department of Gastroenterology, University Hospitals of North Midlands, Stoke on Trent, UK. · Medizinische Universität Wien, Universitätsklinik für Innere Medizin 3, Vienna, Austria. · Department of Medicine, Unit of Gastroenterology, Haukeland University Hospital, Bergen, Norway. · Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. · Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. · Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Sarajevo, Bosnia and Herzegovina. · Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · Department of Internal Medicine, Martin-Luther-Krankenhaus, Berlin, Germany. · Department of Medicine, Mater Dei Hospital, Tal-Qroqq, Malta. · Uni Research Health, Research Unit for General Practice, Bergen, Norway. · Leeds Institute of Biomedical and Clinical Sciences, University of Leeds and Leeds Gastroenterology Institute, Leeds Teaching Hospitals Trust, Leeds, UK. · Centre for Gastrointestinal Sciences, University of Manchester, Manchester, UK. · Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA. ·Neurogastroenterol Motil · Pubmed #27319981.

ABSTRACT: BACKGROUND: Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity, immunity, epithelial permeability and gastrointestinal microflora. Such complexity means there is currently no specific reliable biomarker for IBS, and thus IBS continues to be diagnosed and classified according to symptom based criteria, the Rome Criteria. Carefully phenotyping and characterisation of a 'large' pool of IBS patients across Europe and even the world however, might help identify sub-populations with accuracy and consistency. This will not only aid future research but improve tailoring of treatment and health care of IBS patients. PURPOSE: The aim of this position paper is to discuss the requirements necessary to standardize the process of selecting and phenotyping IBS patients and how to organise the collection and storage of patient information/samples in such a large multi-centre pan European/global study. We include information on general demographics, gastrointestinal symptom assessment, psychological factors, quality of life, physiological evaluation, genetic/epigenetic and microbiota analysis, biopsy/blood sampling, together with discussion on the organisational, ethical and language issues associated with implementing such a study. The proposed approach and documents selected to be used in such a study was the result of a thoughtful and thorough four-year dialogue amongst experts associated with the European COST action BM1106 GENIEUR (www.GENIEUR.eu).

2 Review Irritable bowel syndrome. 2016

Enck, Paul / Aziz, Qasim / Barbara, Giovanni / Farmer, Adam D / Fukudo, Shin / Mayer, Emeran A / Niesler, Beate / Quigley, Eamonn M M / Rajilić-Stojanović, Mirjana / Schemann, Michael / Schwille-Kiuntke, Juliane / Simren, Magnus / Zipfel, Stephan / Spiller, Robin C. ·Department of Internal Medicine VI (Psychosomatic Medicine and Psychotherapy), University Hospital Tübingen, Tübingen, Germany. · Wingate Institute of Neurogastroenterology, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, Bologna, Italy. · Department of Behavioural Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. · Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. · Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, Houston, Texas, USA. · Department of Biochemical Engineering and Biotechnology, Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia. · Department of Human Biology, Technical University Munich, Freising-Weihenstephan, Germany. · Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham, UK. ·Nat Rev Dis Primers · Pubmed #27159638.

ABSTRACT: Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort, stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities. Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases, and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy. Although the underlying pathogenesis is far from understood, aetiological factors include increased epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and genetics, and altered brain-gut interactions. IBS considerably affects quality of life and imposes a profound burden on patients, physicians and the health-care system. The past decade has seen remarkable progress in our understanding of functional bowel disorders such as IBS that will be summarized in this Primer.

3 Review Lessons learned--resolving the enigma of genetic factors in IBS. 2016

Gazouli, Maria / Wouters, Mira M / Kapur-Pojskić, Lejla / Bengtson, May-Bente / Friedman, Eitan / Nikčević, Gordana / Demetriou, Christiana A / Mulak, Agata / Santos, Javier / Niesler, Beate. ·Department of Basic Sciences, Laboratory of Biology, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece. · Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Herestraat 49, Leuven 3000, Belgium. · Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Kemalbegova 10, 71.000 Sarajevo, Bosnia and Herzegovina. · Vestfold Hospital Trust, Tønsberg, Department of Internal Medicine, Division of Gastroenterology, P.O. Box 2168, 3103 Tønsberg, Norway. · The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Centre, 52621 Tel-Hashomer, Israel. · Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 23 11010 Belgrade, Serbia. · Department of Electron Microscopy / Molecular Pathology, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus. · Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland. · Neuro-immuno-gastroenterology Lab, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca. Department of Gastroenterology, Hospital Universitari Vall d'Hebron &Facultat de Medicina, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain. · Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #26726033.

ABSTRACT: IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.

4 Review 5-HT(3) receptors: potential of individual isoforms for personalised therapy. 2011

Niesler, Beate. ·Institute of Human Genetics, Department of Human Molecular Genetics, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. beate.niesler@med.uni-heidelberg.de ·Curr Opin Pharmacol · Pubmed #21345729.

ABSTRACT: Serotonin type 3 (5-HT(3)) receptors are ligand-gated ion channels built by five subunits of diverse composition. In humans, five subunits exist (5-HT3A-E) which are encoded by the genes HTR3A-E and are expressed in various isoforms. Recently, the importance of factors influencing receptor expression became clear, such as chaperones and microRNAs. Owing to their expression profile and physiological functions, 5-HT(3) receptors have been implicated in irritable bowel syndrome (IBS) and psychiatric disorders. Interestingly, HTR3 variants have now been shown to be associated with these conditions. This underlines the potential of 5-HT(3) receptors as therapeutic targets and may enable personalised therapies in the future.

5 Article miR-16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea. 2017

Martínez, Cristina / Rodiño-Janeiro, Bruno K / Lobo, Beatriz / Stanifer, Megan L / Klaus, Bernd / Granzow, Martin / González-Castro, Ana M / Salvo-Romero, Eloisa / Alonso-Cotoner, Carmen / Pigrau, Marc / Roeth, Ralph / Rappold, Gudrun / Huber, Wolfgang / González-Silos, Rosa / Lorenzo, Justo / de Torres, Inés / Azpiroz, Fernando / Boulant, Steeve / Vicario, María / Niesler, Beate / Santos, Javier. ·Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. · Digestive System Research Unit, Institut de Recerca Vall d'Hebron, Barcelona, Spain. · Facultat de Medicina, Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. · Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany. · European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. · Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. · COST Action BM1106 Genes in Irritable Bowel Syndrome (GENIEUR) European Research Network. · nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. · Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany. · Department of Pathology, Facultat de Medicina, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. · Research Group 'Cellular Polarity and Viral Infection' (F140), German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Gut · Pubmed #28082316.

ABSTRACT: OBJECTIVE: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs. DESIGN: Healthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells. RESULTS: IBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CONCLUSIONS: Modulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post-transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms.

6 Article No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome. 2015

Romero, Philipp / Schmitteckert, Stefanie / Wouters, Mira M / Houghton, Lesley A / Czogalla, Bastian / Sayuk, Gregory S / Boeckxstaens, Guy E / Guenther, Patrick / Holland-Cunz, Stefan / Niesler, Beate. ·Department of Surgery, Division of Paediatric Surgery, University of Heidelberg, Heidelberg, Germany. Philipp.Romero@med.uni-heidelberg.de. · Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany. S.Schmitteckert@med.uni-heidelberg.de. · TARGID, University Hospital Leuven, Leuven, Belgium. mira.wouters@med.kuleuven.be. · University of Manchester, Manchester, UK & Mayo Clinic, Jacksonville, USA. Houghton.Lesley@mayo.edu. · Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany. bastian.czogalla@med.uni-heidelberg.de. · Washington University School of Medicine, St. Louis, USA. gsayuk@dom.wustl.edu. · TARGID, University Hospital Leuven, Leuven, Belgium. guy.boeckxstaens@med.kuleiven.be. · Department of Surgery, Division of Paediatric Surgery, University of Heidelberg, Heidelberg, Germany. Patrick.Guenther@med.uni-heidelberg.de. · Department of Paediatric Surgery, University of Basel, Basel, Switzerland. Stefan.Holland-Cunz@ukbb.ch. · Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany. Beate.Niesler@med.uni-heidelberg.de. ·BMC Med Genet · Pubmed #26654249.

ABSTRACT: BACKGROUND: The calcium-sensing receptor (CaSR) is a calcium (Ca(2+)) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca(2+)/Mg(2+)- homeostasis and senses interstitial Ca(2+) levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. METHODS: We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. RESULTS: Genotype frequencies showed no association in the three genotyped case-control samples, neither with IBS nor with IBS subtypes. CONCLUSIONS: Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca(2+) levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies.

7 Article Catecholaminergic Gene Polymorphisms Are Associated with GI Symptoms and Morphological Brain Changes in Irritable Bowel Syndrome. 2015

Orand, Alexa / Gupta, Arpana / Shih, Wendy / Presson, Angela P / Hammer, Christian / Niesler, Beate / Heendeniya, Nuwanthi / Mayer, Emeran A / Chang, Lin. ·Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. · Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. · Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States of America. · Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. ·PLoS One · Pubmed #26288143.

ABSTRACT: BACKGROUND: Genetic and environmental factors contribute to the pathophysiology of irritable bowel syndrome (IBS). In particular, early adverse life events (EALs) and the catecholaminergic system have been implicated. AIMS: To investigate whether catecholaminergic SNPs with or without interacting with EALs are associated with: 1) a diagnosis of IBS, 2) IBS symptoms and 3) morphological alterations in brain regions associated with somatosensory, viscerosensory, and interoceptive processes. METHODS: In 277 IBS and 382 healthy control subjects (HCs), 11 SNPs in genes of the catecholaminergic signaling pathway were genotyped. A subset (121 IBS, 209 HCs) underwent structural brain imaging (magnetic resonance imaging [MRI]). Logistic and linear regressions evaluated each SNP separately and their interactions with EALs in predicting IBS and GI symptom severity, respectively. General linear models determined grey matter (GM) alterations from the SNPs and EALs that were predictive of IBS. RESULTS: 1) DIAGNOSIS: There were no statistically significant associations between the SNPs and IBS status with or without the interaction with EAL after adjusting for multiple comparisons. 2) SYMPTOMS: GI symptom severity was associated with ADRA1D rs1556832 (P = 0.010). 3) Brain morphometry: In IBS, the homozygous genotype of the major ADRA1D allele was associated with GM increases in somatosensory regions (FDR q = 0.022), left precentral gyrus (q = 0.045), and right hippocampus (q = 0.009). In individuals with increasing sexual abuse scores, the ADRAβ2 SNP was associated with GM changes in the left posterior insula (q = 0.004) and left putamen volume (q = 0.029). CONCLUSION: In IBS, catecholaminergic SNPs are associated with symptom severity and morphological changes in brain regions concerned with sensory processing and modulation and affect regulation. Thus, certain adrenergic receptor genes may facilitate or worsen IBS symptoms.

8 Article A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome. 2015

Czogalla, B / Schmitteckert, S / Houghton, L A / Sayuk, G S / Camilleri, M / Olivo-Diaz, A / Spiller, R / Wouters, M M / Boeckxstaens, G / Bermejo, J Lorenzo / Niesler, B. ·Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. ·Neurogastroenterol Motil · Pubmed #25824902.

ABSTRACT: BACKGROUND: To 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. METHODS: We 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 RESULTS: The 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 & INFERENCES: Our 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.

9 Article Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts. 2015

Ek, Weronica E / Reznichenko, Anna / Ripke, Stephan / Niesler, Beate / Zucchelli, Marco / Rivera, Natalia V / Schmidt, Peter T / Pedersen, Nancy L / Magnusson, Patrik / Talley, Nicholas J / Holliday, Elizabeth G / Houghton, Lesley / Gazouli, Maria / Karamanolis, George / Rappold, Gudrun / Burwinkel, Barbara / Surowy, Harald / Rafter, Joseph / Assadi, Ghazaleh / Li, Ling / Papadaki, Evangelia / Gambaccini, Dario / Marchi, Santino / Colucci, Rocchina / Blandizzi, Corrado / Barbaro, Raffaella / Karling, Pontus / Walter, Susanna / Ohlsson, Bodil / Tornblom, Hans / Bresso, Francesca / Andreasson, Anna / Dlugosz, Aldona / Simren, Magnus / Agreus, Lars / Lindberg, Greger / Boeckxstaens, Guy / Bellini, Massimo / Stanghellini, Vincenzo / Barbara, Giovanni / Daly, Mark J / Camilleri, Michael / Wouters, Mira M / D'Amato, Mauro. ·Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. · Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. · Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. · Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia. · Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester, UK Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA. · Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Academic Department of Gastroenterology, School of Medicine, University of Athens, Athens, Greece. · Molecular Epidemiology Group, German Cancer Research Centre (DKFZ) Heidelberg, Heidelberg, Germany Division of Molecular Biology of Breast Cancer, Department of Gynaecology and Obstetrics, University Women's Clinic, University Heidelberg, Heidelberg, Germany. · Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy. · Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy. · Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy. · Department of Medicine, Umeå, University, Umeå, Sweden. · Division of Gastroenterology, Institution of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. · Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden. · Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. · Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Stress Research Institute, Stockholm University, Stockholm, Sweden. · Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. · Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium. · Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA. ·Gut · Pubmed #25248455.

ABSTRACT: OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11,326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

10 Article The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome. 2011

Kilpatrick, Lisa A / Labus, Jennifer S / Coveleskie, Kristen / Hammer, Christian / Rappold, Gudrun / Tillisch, Kirsten / Bueller, Joshua A / Suyenobu, Brandall / Jarcho, Johana M / McRoberts, Jim A / Niesler, Beate / Mayer, Emeran A. ·Center for Neurobiology of Stress, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. lisa@lisakilpatrick.com ·Gastroenterology · Pubmed #21420406.

ABSTRACT: BACKGROUND & AIMS: 5-Hydroxytryptamine (5-HT)3 receptor (5-HT3R) antagonists are effective in treating patients with irritable bowel syndrome (IBS) and have anxiolytic effects. Their therapeutic effects are related, in part, to reducing amygdala engagement during expected visceral pain. A single nucleotide polymorphism in HTR3A, c.-42C>T;(C178T; rs1062613), is associated with altered reactivity of the amygdala during emotional face processing in healthy subjects (controls). We evaluated the influence of this single nucleotide polymorphism on amygdala reactivity to emotional faces and nonemotional stimuli in female patients with IBS and controls. METHODS: We measured brain responses during an affect-matching paradigm in 54 women (26 with IBS, 29 controls) using functional magnetic resonance imaging. We examined associations between HTR3A c.-42C>T genotype (C/C vs T carrier) and responses in amygdala and other regions of brain that expressed high levels of 5-HT3R. RESULTS: The C/C genotype was associated with greater anxiety symptoms in patients with IBS and controls and increased activation of the amygdala under emotional and nonemotional conditions. Among patients with IBS, C/C genotype was associated with greater symptom ratings. A subset of IBS patients with the C/C genotype had increased amygdala responses to nonemotional stimuli, compared with other subjects with C/C genotype. CONCLUSIONS: Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared with T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and nonemotional tasks. This polymorphism was associated with severity of IBS symptoms. Although this genotype is not sufficient for diagnosis of IBS, it is associated with severity of symptoms.

11 Article 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene and irritable bowel syndrome: effect of bowel habit and sex. 2010

Niesler, Beate / Kapeller, Johannes / Fell, Catherine / Atkinson, Wendy / Möller, Dorothee / Fischer, Christine / Whorwell, Peter / Houghton, Lesley A. ·Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany. ·Eur J Gastroenterol Hepatol · Pubmed #19561511.

ABSTRACT: BACKGROUND: Conflicting data exist on the association between functional polymorphisms in the serotonin reuptake transporter (SERT) gene (SLC6A4) and irritable bowel syndrome (IBS). This may be partly because of small participant numbers and varying ethnic origin and sex within the cohorts studied. AIM: To reassess the potential association between the SERT polymorphisms 5-HTTLPR and STin2 in both male and female IBS patients with diarrhoea (IBS-D) and constipation (IBS-C) compared with healthy volunteers. METHODS: In this case-control study, 196 Caucasian Rome II IBS patients [97 IBS-D (aged 18-66 years; 67 female) and 99 IBS-C (aged 18-65 years; 95 female)] and 92 Caucasian healthy volunteers (aged 18-63 years; 60 female) from the UK had genomic DNA extracted from peripheral blood and the 5-HTTLPR and STin2 polymorphisms genotyped. RESULTS: The frequency of the 5-HTTLPR (ss) genotype was slightly lower in both IBS-D (16.5%) and IBS-C (14.3%) patients compared with controls (23.9%), although not significantly (POur finding that male IBS-D patients have a reduced frequency of the 5-HTTLPR (ss) genotype contradicts three earlier studies of a similar size, which did not take sex into account. Therefore, replication studies in even larger cohorts, stratifying for sex and endophenotypes, after assessing physiological and psychological traits, are required to unravel the contribution of SERT polymorphisms to the IBS phenotype.

12 Article First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. 2008

Kapeller, Johannes / Houghton, Lesley A / Mönnikes, Hubert / Walstab, Jutta / Möller, Dorothee / Bönisch, Heinz / Burwinkel, Barbara / Autschbach, Frank / Funke, Benjamin / Lasitschka, Felix / Gassler, Nikolaus / Fischer, Christine / Whorwell, Peter J / Atkinson, Wendy / Fell, Catherine / Büchner, Karl J / Schmidtmann, Marco / van der Voort, Ivo / Wisser, Anna-Sophia / Berg, Thomas / Rappold, Gudrun / Niesler, Beate. ·Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. ·Hum Mol Genet · Pubmed #18614545.

ABSTRACT: Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.