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Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

Genes & Immunity volume 13, pages 321–327 (2012)Cite this article

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Abstract

Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg689 (MSPwt) and Cys689 (MSPmut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSPmut significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.

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Acknowledgements

This article includes experimental work performed by Friederike Häuser in fulfilment of the requirements for her doctoral thesis. This work was supported by the research and education funds of the University Clinic of Mainz (MAIFOR program, Julia K Bickmann).

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Authors and Affiliations

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

    F Häuser, C Deyle, D Berard, C Neukirch, C Glowacki, J K Bickmann, J J Wenzel, K J Lackner & H Rossmann

  2. Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany

    J J Wenzel

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  1. F Häuser
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Häuser, F., Deyle, C., Berard, D. et al. Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease. Genes Immun 13, 321–327 (2012). https://doi.org/10.1038/gene.2011.88

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