Περίληψη:
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.
Συγγραφείς:
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.
Λέξεις-κλειδιά:
messenger RNA, adult; Article; controlled study; female; follow up; gene expression; gene function; genetic association; genetic risk; genotype; GRID2IP gene; human; irritable colon; KDELR2 gene; major clinical study; male; priority journal; quality control; quantitative trait locus; questionnaire; real time polymerase chain reaction; rectum biopsy; single nucleotide polymorphism; Swedish citizen; case control study; clinical trial; cohort analysis; genetics; international cooperation; irritable colon; middle aged; multicenter study, Adult; Case-Control Studies; Cohort Studies; Female; Genome-Wide Association Study; Humans; Internationality; Irritable Bowel Syndrome; Male; Middle Aged
