PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus

Abstract

ObjectivesPsoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA.MethodsA total of 15 single nucleotide polymorphisms were selected (PImmunochip <1×10−4) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity.ResultsWe found genome-wide significant association to rs2476601, mapping to PTPN22 (p=1.49×10−9, OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2×10−4). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27×10−9).ConclusionsFor the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis.

Identification of PTPN22,ST6GAL1 and JAZF1 as psoriasis risk genes demonstrates shared pathogenesis between psoriasis and diabetes

“…More recently, Bowes J et al. also demonstrated the association of rs2476601 (R620W) with psoriatic arthritis, but not psoriasis vulgaris . In addition, another two SNPs (rs3789604 and rs1217414) within the PTPN22 region were found to be associated with type I psoriasis, suggesting the role of this gene in early‐onset psoriasis .…”

Integration of expression quantitative trait loci and pleiotropy identifies a novel psoriasis susceptibility gene, PTPN1

“…The PTPN1 gene is the founding member of the protein tyrosine phosphatase (PTP) family and acts as a regulatory signaling molecule in a variety of cellular processes, including B and T cell growth, differentiation, mitotic cycle, and oncogenic transformation . One PTP family member, PTPN22 , is associated in GWAS with several autoimmune diseases, including psoriasis, arthritis and rheumatoid arthritis . PTPN1 has been reported to play a role in certain cancers .…”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…A genome-wide association study has identified an association between both psoriasis and PsA and TRAF3IP2, a gene encoding a protein involved in IL-17 signaling and interacting with members of the Rel/NF-kB transcription factor family [87,88]. Moreover, a significant association in PsA has been found with rs2476601, mapping to PTPN22, but without an association with psoriasis [89]. A large GWAS and meta-analysis of this study with three other GWASs, encompassing a total of 9293 psoriasis vulgaris case subjects, 3061 PsA case subjects, 3110 only cutaneous psoriasis case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with only cutaneous psoriasis at genome-wide GW significance (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for only cutaneous psoriasis).…”