Abstract
The 1858T allele in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus shows one of the strongest and most consistent genetic associations with autoimmune diseases. We synthesized all meta-analyses reporting a genetic association of the PTPN22 1858T C/T polymorphism with autoimmune diseases. This work examined their validity to discover false positive results under Bayesian methods. We conducted a PubMed search to identify relevant publications and extracted the respective results, published until 30 November 2018. In observational studies, the associations of 1858 C/T genetic variant were noteworthy for 12 autoimmune or autoimmunity-related diseases (rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, juvenile idiopathic arthritis, Crohn’s disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vitiligo, Graves’ disease, myasthenia gravis, Addison’s disease, giant cell arteritis, and endometriosis). In contrast, we could not confirm the noteworthiness for eight diseases (systemic sclerosis, psoriasis, Behçet’s disease, autoimmune thyroid disease, alopecia areata, Sjögren’s syndrome, inflammatory bowel disease, and ankylosing spondylitis). From the meta-analysis of genome-wide association studies (GWAS) with a p-value < 5 × 10−8, findings verified noteworthiness for all autoimmune diseases (psoriatic arthritis, myasthenia gravis, juvenile idiopathic arthritis and rheumatoid arthritis). The results from meta-analysis of GWAS showing a p-value ranging between 0.05 and 5 × 10−8 were noteworthy under both Bayesian approaches (ANCA-associated vasculitis, type 1 diabetes mellitus, giant cell arteritis and juvenile idiopathic arthritis). Re-analysis of observational studies and GWAS by Bayesian approaches revealed the noteworthiness of all significant associations observed by GWAS, but noteworthiness could not be confirmed for all associations found in observational studies.
Highlights
The 1858T allele in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus has a strong and consistent genetic association with autoimmune diseases
The genetic association of the PTPN22 1858 C/T variant was evaluated in a total of 20 autoimmune or autoimmunity-related diseases
Most studies focused on rheumatoid arthritis (RA, n = 13), systemic lupus erythematosus (SLE, n = 7) and type 1 diabetes mellitus (T1DM, n = 8), followed by five on juvenile idiopathic arthritis (JIA), 5 on Crohn’s disease (CD), 4 on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, 3 on vitiligo, 3 on systemic sclerosis (SSc), 3 on Graves’ disease (GD), 3 on myasthenia gravis (MG), 3 on Addison’s disease (AD), 2 on psoriasis, 1 study on Behcet’s disease (BD), 1 on endometriosis, 1 on autoimmune thyroid disease (AITD), 1 on inflammatory bowel disease (IBD), 1 on giant cell arteritis (GCA), 1 on alopecia areata (AA), 1 on Sjögren’s syndrome (SS), and 1 study on ankylosing spondylitis (AS)
Summary
The 1858T allele in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus has a strong and consistent genetic association with autoimmune diseases. This phosphatase is expressed in hematopoietic cells and in immune cells with highest levels found in neutrophils and natural killer cells [1]. The SNP rs2476601 is a change of cytosine to thymidine at nucleotide 1858 (C1858T) which results in an amino acid change from arginine to tryptophan at codon 620 (R620W) This codon is located in the polyproline binding motif P1 [2,3]. Since 1858 C/T polymorphism results in immune responses against autoantigens [3], genetic association is proposed to be restricted to disorders that have a strong autoantibody component
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