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Inflammatory bowel disease (IBD) locus 12: is glutathione peroxidase-1 (GPX1) the relevant gene?

Genes & Immunity volume 16, pages 571–575 (2015)Cite this article

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Abstract

Genome-wide association studies have identified and repeatedly confirmed the association of rs3197999 in MST1 with inflammatory bowel disease (IBD). However, the underlying pathophysiology remains unclear. rs3197999 is a non-synonymous single-nucleotide polymorphism which modifies the function of macrophage stimulating protein-1 (MST1). We show by haplotyping that rs3197999 is in linkage disequilibrium with rs1050450 in GPX1, with almost complete cosegregation of the minor alleles. As shown by immunoassay, rs3197999 influences the MST-1 level in serum. But also rs1050450 causes an amino acid exchange in glutathione peroxidase 1 (GPx-1) and reduced activity of this antioxidant enzyme. The association of GPx deficiency and IBD in mice was already shown. We propose that GPx-1 is a better candidate than MST1 for the pathophysiologic link between IBD locus 12 and IBD.

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References

  1. Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 2008; 1: 131–138.

    Article  CAS  Google Scholar 

  2. Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T et al. Genome-Wide Association Analysis in Primary Sclerosing Cholangitis. Gastroenterology 2010; 138: 1102–1111.

    Article  Google Scholar 

  3. Melum E, Franke A, Schramm C, Weismuller TJ, Gotthardt DN, Offner FA et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011; 43: 17–19.

    Article  CAS  Google Scholar 

  4. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 2007; 39: 830–832.

    Article  CAS  Google Scholar 

  5. Danilkovitch A, Leonard EJ . Kinases involved in MSP/RON signaling. J Leukoc Biol 1999; 65: 345–348.

    Article  CAS  Google Scholar 

  6. Wang MH, Zhou YQ, Chen YQ . Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scand J Immunol 2002; 56: 545–553.

    Article  CAS  Google Scholar 

  7. Häuser F, Deyle C, Berard D, Neukirch C, Glowacki C, Bickmann JK et al. Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease. Genes Immun 2012; 13: 321–327.

    Article  Google Scholar 

  8. Kauder SE, Santell L, Mai E, Wright LY, Luis E, N'Diaye EN et al. Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele. PLoS ONE 2013; 8: e83958.

    Article  Google Scholar 

  9. Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118–1125.

    Article  CAS  Google Scholar 

  10. Latiano A, Palmieri O, Corritore G, Valvano MR, Bossa F, Cucchiara S et al. Variants at the 3p21 locus influence susceptibility and phenotype both in adults and early-onset patients with inflammatory bowel disease. Inflamm Bowel Dis 2010; 16: 1108–1117.

    Article  Google Scholar 

  11. Ravn-Haren G, Olsen A, Tjonneland A, Dragsted LO, Nexo BA, Wallin H et al. Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study. Carcinogenesis 2006; 27: 820–825.

    Article  CAS  Google Scholar 

  12. Hu YJ, Diamond AM . Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res 2003; 63: 3347–3351.

    CAS  PubMed  Google Scholar 

  13. Esworthy RS, Aranda R, Martín MG, Doroshow JH, Binder SW, Chu F . Mice with combined disruption of Gpx1 andGpx2 genes have colitis. Am J Physiol Gastrointest Liver Physiol 2001; 281: G848–G855.

    Article  CAS  Google Scholar 

  14. Kaushal N, Kudva AK, Patterson AD, Chiaro C, Kennett MJ, Desai D et al. Crucial role of macrophage selenoproteins in experimental colitis. J Immunol 2014; 193: 3683–3692.

    Article  CAS  Google Scholar 

  15. Speckmann B, Steinbrenner H . Selenium and selenoproteins in inflammatory bowel diseases and experimental colitis. Inflamm Bowel Dis 2014; 20: 1110–1119.

    PubMed  Google Scholar 

  16. Jablonska E, Gromadzinska J, Reszka E, Wasowicz W, Sobala W, Szeszenia-Dabrowska N et al. Association between GPx1 Pro198Leu polymorphism, GPx1 activity and plasma selenium concentration in humans. Eur J Nutr 2009; 48: 383–386.

    Article  CAS  Google Scholar 

  17. Karunasinghe N, Han D, Zhu S, Yu J, Lange K, Duan H et al. Serum selenium and single-nucleotide polymorphisms in genes for selenoproteins: relationship to markers of oxidative stress in men from Auckland, New Zealand. Genes Nutr 2012; 7: 179–190.

    Article  CAS  Google Scholar 

  18. Bera S, Weinberg F, Ekoue DN, Ansenberger-Fricano K, Mao M, Bonini MG et al. Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function. Cancer Res 2014; 74: 5118–5126.

    Article  CAS  Google Scholar 

  19. Wild PS, Sinning CR, Roth A, Wilde S, Schnabel RB, Lubos E et al. Distribution and categorization of left ventricular measurements in the general population: results from the population-based Gutenberg Heart Study. Circ Cardiovasc Imaging 2010; 3: 604–613.

    Article  Google Scholar 

  20. Paglia DE, Valentine WN . Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967; 70: 158–169.

    CAS  PubMed  Google Scholar 

  21. Garnier S, Truong V, Brocheton J, Zeller T, Rovital M, Wild PS et al. Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes. PLoS Genet 2013; 9: e1003240.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany

    F Häuser, H Rossmann, S Neuwirth & K J Lackner

  2. Department of Medicine II, Preventive Cardiology and Preventive Medicine, University Medical Center Mainz, Mainz, Germany

    D Laubert-Reh & P S Wild

  3. Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

    P S Wild

  4. German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany

    P S Wild

  5. Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany

    T Zeller, C Müller & S Blankenberg

  6. German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany

    T Zeller & S Blankenberg

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  1. F Häuser
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  2. H Rossmann
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Correspondence to H Rossmann.

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Häuser, F., Rossmann, H., Laubert-Reh, D. et al. Inflammatory bowel disease (IBD) locus 12: is glutathione peroxidase-1 (GPX1) the relevant gene?. Genes Immun 16, 571–575 (2015). https://doi.org/10.1038/gene.2015.35

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  • DOI: https://doi.org/10.1038/gene.2015.35

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