FULL PAPER The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status AT Lee 1 , W Li 1 , A Liew 1 , C Bombardier 2 , M Weisman 3 , EM Massarotti 4 , J Kent 5 , F Wolfe 6 , AB Begovich 7 and PK Gregersen 1 1 North Shore-LIJ Research Institute, Manhasset, NY, USA; 2 University of Toronto, Toronto, Canada; 3 Cedars Sinai Hospital, Los Angeles, CA, USA; 4 Tufts New England Medical Center, Boston, MA, USA; 5 Abbott Laboratories, Abbott Park, IL, USA; 6 National Data Bank for Rheumatic Diseases, Wichita, KS, USA; 7 Celera Diagnostics, Alameda, CA, USA 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 ¼ 1.75, 95% CI 1.46–2.10, P ¼ 1.3  10 9 ). The PTPN22 risk allele was not significantly associated with RF negative disease (OR ¼ 1.19, 95% CI 0.92–1.53, P ¼ 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 ¼ 4.57, 95% CI 2.35–8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles. Genes and Immunity (2005) 6, 129–133. doi:10.1038/sj.gene.6364159 Published online 23 December 2004 Keywords: rheumatoid arthritis; PTPN22; RF-positive; genetic association; HLA; risk allele Introduction Rheumatoid arthritis (RA) affects up to 1% of the adult population worldwide, making it the most common systemic autoimmune disease. It is two to three times more prevalent in women than in men and is character- ized by immune-cell-mediated destruction of the joint architecture. Long-term prognosis is generally poor with joint destruction affecting approximately 80% of affected individuals within 20 years. 1–3 Rheumatoid factor (RF), which is an immunoglobulin directed against the Fc portion of IgG, is found in over 70% of patients with RA; high RF may confer a worse prognosis. RA patients who are RF positive tend to have more aggressive erosive bone and joint disease than those who are RF negative. 4,5 The presence of RF may precede clinical diagnosis by many years, indicating that its production may be associated with an early key event in the autoimmune response. 6–9 It is presently unclear to what extent RF positive disease differs from RF negative disease in terms of disease pathogenesis, and aside from differences in HLA associations, there are no clearly established genetic differences between the two sub- phenotypes of RA. In a recent case–control association study, Begovich et al 10 found a strong association of the PTPN22 1858C/T (rs2476601) single-nucleotide polymorphism (SNP) with RA. The presence of the minor 1858T allele increased the relative risk for RA almost two-fold. The carrier frequency of the 1858T risk allele in Caucasians with RA was 28% while this allele was present in approxi- mately 17% of Caucasian controls. In this original report, the predominant association appeared to be with RF positive RA, although the number of subjects with RF negative disease was too low to reach a definitive conclusion. We have now examined this issue in a large set of both RF positive and RF negative rheumatoid arthritis patients and controls. We document that PTPN22 is specifically associated with RF positive RA, and displays a marked dose effect. Interestingly, despite the association of HLA-DRB1 with rheumatoid factor production in our RA population, there is no evidence of an association between PTPN22 and the RA associated HLA-DRB1 alleles. Received 20 September 2004; revised 1 November 2004; accepted 2 November 2004; published online 23 December 2004 Correspondence: Dr AT Lee, North Shore LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA. E-mail: ANLEE@NSHS.EDU Genes and Immunity (2005) 6, 129–133 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene