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Positional identification of Ncf1 as a gene that regulates arthritis severity in rats

Nature Genetics volume 33, pages 2532 (2003) | Download Citation

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Abstract

The identification of genes underlying quantitative-trait loci (QTL) for complex diseases, such as rheumatoid arthritis, is a challenging and difficult task for the human genome project. Through positional cloning of the Pia4 QTL in rats, we found that a naturally occurring polymorphism of Ncf1 (encoding neutrophil cytosolic factor 1, a component of the NADPH oxidase complex) regulates arthritis severity. The disease-related allele of Ncf1 has reduced oxidative burst response and promotes activation of arthritogenic T cells. Pharmacological treatment with substances that activate the NADPH oxidase complex is shown to ameliorate arthritis. Hence, Ncf1 is associated with a new autoimmune mechanism leading to severe destructive arthritis, notably similar to rheumatoid arthritis in humans.

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Acknowledgements

We thank C. Palestro for taking care of the rats; M. Svejme for histopathologic analyses; M. Neptin and J. Arenhag for cDNA sequencing and SNP analysis; Anticimex in Malmö, I. Klöting and J. Holmdahl for providing wild rat DNA; K.-K. Levan and D. Wedekind for inbred strain rat DNA; L. Andersson for advice about positional cloning; L. Peltonen and H. Luthman for critical reading and valuable suggestions; and M. Rowley and A. Threschow for linguistic help. This work was supported in part by the Anna Greta Crafoord, King Gustaf V's 80-year, the Nilsson-Ehle, the Kock and Österlund Foundations; the Swedish Association against Rheumatism; Arexis AB; the Swedish Medical Research Council; the Swedish Society for Medical Research; the Strategic Research Foundation; and the European Union.

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  1. Section for Medical Inflammation Research and Department of Cell and Molecular Biology, Sölvegatan 19, I11 BMC, Lund University, S-22184 Lund, Sweden.

    • Peter Olofsson
    • , Jens Holmberg
    • , Jesper Tordsson
    • , Shemin Lu
    •  & Rikard Holmdahl
  2. Section for Molecular Pathogenesis, Department of Cell and Molecular Biology, Sölvegatan 19, I11 BMC, Lund University, S-22184 Lund, Sweden.

    • Bo Åkerström

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Competing interests

A patent has been submitted by Arexis AB, of which R.H. is one of the founders.

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Correspondence to Rikard Holmdahl.

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https://doi.org/10.1038/ng1058