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  • 1. Ek, Weronica E.
    et al.
    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
    Törnblom, Hans
    Bresso, Francesca
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Dlugosz, Aldona
    Simrén, Magnus
    Agréus, Lars
    Lindberg, Greger
    Boeckxstaens, Guy
    Bellini, Massimo
    Stanghellini, Vincenzo
    Barbara, Giovanni
    Daly, Mark J.
    Camilleri, Michael
    Wouters, Mira M.
    D'Amato, Mauro
    Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts2015In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, no 11, 1774-1782 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 2. Henström, Maria
    et al.
    Hadizadeh, Fatemeh
    Beyder, Arthur
    Bonfiglio, Ferdinando
    Zheng, Tenghao
    Assadi, Ghazaleh
    Rafter, Joseph
    Bujanda, Luis
    Agreus, Lars
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska institutet, Sweden.
    Dlugosz, Aldona
    Lindberg, Greger
    Schmidt, Peter T.
    Karling, Pontus
    Ohlsson, Bodil
    Talley, Nicholas J.
    Simren, Magnus
    Walter, Susanna
    Wouters, Mira
    Farrugia, Gianrico
    D'Amato, Mauro
    TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M2017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 9, 1725-1727 p.Article in journal (Refereed)
  • 3. Jankipersadsing, Soesma A.
    et al.
    Hadizadeh, Fatemeh
    Bonder, Marc Jan
    Tigchelaar, Ettje F.
    Deelen, Patrick
    Fu, Jingyuan
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Agreus, Lars
    Walter, Susanna
    Wijmenga, Cisca
    Hysi, Pirro
    D'Amato, Mauro
    Zhernakova, Alexandra
    A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency2017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 4, 756-758 p.Article in journal (Refereed)
  • 4. Quince, Christopher
    et al.
    Lundin, Elin E.
    Andreasson, Anna N.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Greco, Dario
    Rafter, Joseph
    Talley, Nicholas J.
    Agreus, Lars
    Andersson, Anders F.
    Engstrand, Lars
    D'Amato, Mauro
    The impact of Crohn's disease genes on healthy human gut microbiota: a pilot study2013In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 62, no 6, 952-954 p.Article in journal (Refereed)
  • 5. Zucchelli, Marco
    et al.
    Camilleri, Michael
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Bresso, Francesca
    Dlugosz, Aldona
    Halfvarson, Jonas
    Törkvist, Leif
    Schmidt, Peter T
    Karling, Pontus
    Ohlsson, Bodil
    Duerr, Richard H
    Simren, Magnus
    Lindberg, Greger
    Agreus, Lars
    Carlson, Paula
    Zinsmeister, Alan R
    D'Amato, Mauro
    Association of TNFSF15 polymorphism with irritable bowel syndrome2011In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 60, no 12, 1671-7 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.

    METHODS: Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case-control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A).

    RESULTS: The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10(-5); OR 1.37) and more pronouncedly, IBS-C (p=8.7×10(-7); OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033).

    CONCLUSIONS: TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.

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