Nature Genetics33, 25 - 32 (2002)
Published online: 2 December 2002; | doi:10.1038/ng1058
Positional identification of Ncf1 as a gene that regulates arthritis severity in rats
Peter Olofsson1, Jens Holmberg1, Jesper Tordsson1, Shemin Lu1, Bo Åkerström2
& Rikard Holmdahl1
1
Section for Medical Inflammation Research and Department of Cell and Molecular Biology, Sölvegatan 19, I11 BMC, Lund University, S-22184 Lund, Sweden.
2
Section for Molecular Pathogenesis, Department of Cell and Molecular Biology, Sölvegatan 19, I11 BMC, Lund University, S-22184 Lund, Sweden.
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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