1. ¹North Shore-LIJ Research Institute, Manhasset, NY, USA
2. ²University of Toronto, Toronto, Canada
3. ³Cedars Sinai Hospital, Los Angeles, CA, USA
4. ⁴Tufts New England Medical Center, Boston, MA, USA
5. ⁵Abbott Laboratories, Abbott Park, IL, USA
6. ⁶National Data Bank for Rheumatic Diseases, Wichita, KS, USA
7. ⁷Celera Diagnostics, Alameda, CA, USA

Correspondence: Dr AT Lee, North Shore LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA. E-mail: ANLEE@NSHS.EDU

Received 20 September 2004; Revised 1 November 2004; Accepted 2 November 2004; Published online 23 December 2004.

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.