Inflammatory bowel disease (IBD) locus 12: is glutathione peroxidase-1 (GPX1) the relevant gene?
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.
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
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F
Häuser
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
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H
Rossmann
Department of Medicine II, Preventive Cardiology and Preventive Medicine, University Medical Center Mainz, Mainz, Germany.
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D
Laubert-Reh
Department of Medicine II, Preventive Cardiology and Preventive Medicine, University Medical Center Mainz, Mainz, Germany.|Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany.
P S
PS
Wild
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
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T
Zeller
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
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C
Müller
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
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S
Neuwirth
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
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S
Blankenberg
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
K J
KJ
Lackner
D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1