PTPN22 Genetic Variation: Evidence for Multiple Variants Associated with Rheumatoid Arthritis

Abstract

The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

Association of PTPN22 single nucleotide polymorphism with rheumatoid arthritis but not with allergic asthma

“…16 It will be interesting, then, to check whether their associations can be reproduced in our sample.…”

Linkage proof for PTPN22 , a rheumatoid arthritis susceptibility gene and a human autoimmunity gene

“…Also, the frequency of the homozygous genotype 1858T/T was too rare in the population investigated, to test for the dose effect on disease risk that has been reported (13,29). The 1858T-negative PTPN22 haplotype that has been recently suggested to be an independent RA susceptibility allele was not investigated (30).…”

“…Rare mutations that might have high penetrance should be searched for and investigated, as the same gene can contribute to a disease not only with a common susceptibility allele of low penetrance, but also with rare deleterious mutations of high penetrance, such as RET gene in Hirschprung disease (33). Such a mutation was reported and needs to be investigated (30). This gene is to be further explored for various populations, to provide accurate genotype association estimates for RA as well as for other autoimmune diseases.…”

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

“…24,25 A recent report indicates that additional variability in the PTPN22 locus may account for a more minor proportion of risk for RA. 26 Aside from PTPN22 and the HLA region, associations with CTLA4 and PADI4 have also been supported in some additional studies, 27 suggesting that these genes may also contribute to RA susceptibility in Caucasian populations, albeit with rather modest relative risks.…”