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

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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Figure 1: Clinical arthritis in Pia4 congenic rats.
Figure 2: Plasma protein levels (mean ± s.e.m.) in Pia4 congenic rats.
Figure 3: Physical mapping and reduction of Pia4 congenic fragment.
Figure 4: Polymorphism and expression of Ncf1.
Figure 5: Functional analysis of Ncf1 by measurement of oxidative burst.
Figure 6: Clinical arthritis 15 d after adoptive transfer of cells taken from spleens of donor rats 12 d after pristane injection.

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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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Correspondence to Rikard Holmdahl.

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

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Olofsson, P., Holmberg, J., Tordsson, J. et al. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet 33, 25–32 (2003). https://doi.org/10.1038/ng1058

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