Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis

Abstract

Our genetic findings strengthen the concept that these groups of patients correspond to etiologically distinct disease entities.

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

“…We found suggestive evidence for association at the PTPN22 locus, as previously noted in EOMG (14,15) (Supplementary Table S3). In contrast, there was only marginal evidence for any association signal for TNIP1 (all P values >0.001 within 100 kb flanking this gene or in r 2 > 0.25), the strongest non-HLA signal we observed in EOMG (15).…”

“…PTPN22 was reported in several studies in MG (14,15,41), reaching GWAS criteria in EOMG (15). This association is with the same coding SNP, rs2476601, as in EOMG, with similar effect sizes (ORs 1.62-1.71), and in multiple other autoimmune diseases including type 1 diabetes mellitus, rheumatoid arthritis (RA) and systemic lupus erythematosus (42)(43)(44).…”

“…We confirmed the association with PTPN22 (14) and identified a novel association with a TNIP1 coding single nucleotide polymorphism (SNP) and defined HLA associations (15). The study mapped the strongest HLA association to HLA-B*08 rather than class II SNPs in linkage disequilibrium (LD) with this class I allele (15).…”

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…Multiple subsequent studies have confirmed the association of this SNP with T1D, with a recent genome wide meta-analysis reporting a p-value of 5.93x10 -80 and an odds ratio (OR) of 1.96 [4]. This variant is associated with multiple autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease, and myasthenia gravis [5][6][7][8]. The 1858T variant is a missense mutation of the coding region, in which cytosine is replaced by thymidine at position 1858, resulting in a change from an arginine (R) at position 620 of the protein to tryptophan (W).…”

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

“…Their presumed low-expression or low-activity genotypes predispose to multiple autoimmune diseases, including type 1 diabetes, [5][6][7][8][9] Graves' disease, 7,8 hypothyroidism, 6,8 systemic lupus erythematosus, 6,10 rheumatoid arthritis, 6,11 and non-thymoma myasthenia gravis (MG). 12 However, the function of PTPN22 in this tolerance failure 13 has become debatable because of the paradoxically stronger inhibition of T-cell activation 14 by the autoimmunity-prone PTPN22 þ 1858T/T ( 620 W) or C/T genotype rather than the protective þ 1858C/C ( 620 R). A previous study on French subjects showed an association of the PTPN22 þ 1858C/T single nucleotide polymorphism with non-thymoma MG without anti-titin antibodies but not with thymoma-associated MG. 12 It has been found that interleukin-2 (IL-2) is expressed in the thymus during T-cell receptor (TCR)-mediated thymocyte apoptosis, and IL-2/IL-2 receptor (IL-2R) signaling is required for intrathymic negative selection of T cells.…”