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Objectives  The Trp 620  allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype ‘5’, haplotype group ‘6–10’ and susceptibility haplotype ‘4’, suggesting the possibility of other  PTPN22  variants involved in the pathogenesis of RA independent of R620W ( rs2476601 ). Our aim was to further investigate this possibility.    Methods  A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms  rs3789607 ,  rs12144309 ,  rs3811021  and  rs12566340  were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.    Results  The protective effect of haplotype 5 was confirmed ( rs3789607 ; (OR = 0.91,  P  = 0.016), and a second protective effect (possibly of haplotype 6) was observed ( rs12144309 ; OR = 0.90,  P  = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed ( rs3811021 ; OR = 0.85,  P  = 1.4×10 −5 ). Haplotypes defined by  rs3789607 ,  rs12144309  and  rs3811021  coalesced with the major allele of  rs12566340  within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested  rs12566340  for association with RA conditional on  rs2476601 ; there was no evidence for an independent effect at  rs12566340  ( P  = 0.76). Similarly, there was no evidence for an independent effect at  rs12566340  in type 1 diabetes ( P  = 0.85).    Conclusions  We have no evidence for a common variant additional to  rs2476601  within the  PTPN22  locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.

The PTPN22 Locus and Rheumatoid Arthritis: No Evidence for an Effect on Risk Independent of Arg620Trp