Abstract
We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46–2.10, P=1.3 × 10−9). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92–1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35–8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.
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Acknowledgements
We would like to acknowledge all RA patients who participated in each of the RA studies. We thank Lyn Maguire for support of the SONORA Project and Marlena Kern for her commitment to SONORA and all the projects within Robert S Boas Center for Genomics and Human Genetics, TL Bugawan and E Trachtenberg for HLA typing, A Chokkalingham and V Carlton for valuable comments on this manuscript, and Abbott Laboratories for financial support of the SONORA study. PKG is supported in part by NIH grants RO1 AR44422 and NO1-AR-2-2263.
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Lee, A., Li, W., Liew, A. et al. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun 6, 129–133 (2005). https://doi.org/10.1038/sj.gene.6364159
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DOI: https://doi.org/10.1038/sj.gene.6364159
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