| Autor: |
Ek, W.E. Reznichenko, A. Ripke, S. Niesler, B. Zucchelli, M. Rivera, N.V. Schmidt, P.T. Pedersen, N.L. Magnusson, P. Talley, N.J. Holliday, E.G. Houghton, L. Gazouli, M. Karamanolis, G. Rappold, G. Burwinkel, B. Surowy, H. Rafter, J. Assadi, G. Li, L. Papadaki, E. Gambaccini, D. Marchi, S. Colucci, R. Blandizzi, C. Barbaro, R. Karling, P. Walter, S. Ohlsson, B. Tornblom, H. Bresso, F. Andreasson, A. Dlugosz, A. Simren, M. Agreus, L. Lindberg, G. Boeckxstaens, G. Bellini, M. Stanghellini, V. Barbara, G. Daly, M.J. Camilleri, M. Wouters, M.M. D'Amato, M. |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Popis: |
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. © 2015, BMJ Publishing Group. All rights reserved. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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