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Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

Genes & Immunity volume 7, pages 11–18 (2006)Cite this article

Abstract

Linkage analyses have implicated chromosome 7p21.3 as a susceptibility region for inflammatory bowel disease (IBD). Recently, the mouse phenotype with diarrhea and goblet cell dysfunction caused by anterior gradient protein 2 dysfunction was reported (European patent WO2004056858). The genes encoding for the human homologues AGR2 and AGR3 are localized on chromosome 7p21.3. The gene structures were verified and mutation detection was performed in 47 IBD patients. A total of 30 single nucleotide polymorphisms (SNPs) were tested for association to ulcerative colitis (UC, N=317) and Crohn's disease (CD, N=631) in a German cohort and verified in a UK cohort of 384 CD and 311 UC patients. An association signal was identified in the 5′ region of the AGR2 gene (most significant SNP hcv1702494, nominal PTDT=0.011, Pcase/control=0.0007, OR=1.34, combined cohort). The risk haplotype carried an odds ratio of 1.43 in the German population (P=0.002). AGR2 was downregulated in UC patients as compared to normal controls (P<0.001) and a trend toward lower expression was seen in carriers of the risk alleles. Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2. In summary, AGR2 represents an interesting new avenue into the etiopathophysiology of IBD and the maintenance of epithelial integrity.

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Acknowledgements

This study was supported by the German National Genome Research Network (NGFN, DHGP), the Competence Network IBD and the Network ‘Fat and metabolism’ of the BmBF, the European Commission (FP5 grant), the German Research Council (DFG For423, Ha 3091/1-1) and the POPGEN population project.

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Authors and Affiliations

  1. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany

    W Zheng, P Rosenstiel, C Sina, R Valentonyte, N Mah, C M Costello, S Schreiber & J Hampe

  2. Kiel Center of the German National Genotyping Platform, Christian-Albrechts-University, Kiel, Germany

    W Zheng, R Valentonyte & J Hampe

  3. Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany

    K Huse & M Platzer

  4. Ingenium Pharmaceuticals AG, Martinsried, Germany

    L Zeitlmann & J Grosse

  5. Gene Mapping Center, MDC Berlin, Germany

    N Ruf & P Nürnberg

  6. Division of Genetics and Molecular Medicine, King's College London, London, UK

    C Onnie & C Mathew

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  1. W Zheng
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Correspondence to J Hampe.

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Zheng, W., Rosenstiel, P., Huse, K. et al. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun 7, 11–18 (2006). https://doi.org/10.1038/sj.gene.6364263

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  • DOI: https://doi.org/10.1038/sj.gene.6364263

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