PTPN22 1858T is not a risk factor for North American Pemphigus vulgaris

Abstract

Alterations in the protein tyrosine phosphatase N22 (PTPN22) gene affect the threshold for lymphocyte activation. The PTPN22 1858T polymorphism leads to uninhibited T-cell receptor cascade propagation. An elevated PTPN22 1858C/T genotype frequency has been correlated with several autoimmune disorders which have T-cell and humoral components. However, a recent Tunisian report demonstrated no association between PTPN22 1858T and patients with Pemphigus vulgaris (PV), an autoantibody-associated blistering disorder. Because PTPN22 1858T allele frequency is known to vary across ethnic populations, we conducted a case-control study investigating the relationship between PTPN22 1858T and PV in North American patients of either Ashkenazi Jewish or Caucasian (non-Ashkenazi) decent. Participant genotype was determined in 102 PV patients and 102 healthy controls by restriction fragment length polymorphism-polymerase chain reaction genotyping. Relationships were calculated using Fisher's exact tests and chi-squared tests. We report that the PTPN22 1858C/T genotype is not significantly associated with PV in either Caucasians (P = 0.83) or Ashkenazi Jews (P = 0.60). Further stratification of the patient population by gender, age of disease onset, HLA-type, family history of autoimmune disease, history of anti-desmoglein (anti-Dsg) 3 or anti-Dsg1 antibody response, history of lesion morphology, and disease duration did not uncover significant associations between the PTPN22 1858T allele and PV subgroups. Our data indicate that the PTPN22 1858T mutation is not associated with PV in the North American population. We do observe an elevation of PTPN22 1858C/T genotype frequency in male PV patients. Further investigation will be required to determine if this trend reaches significance in larger studies.

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

“…103 PV is caused by antibodies against desmoglein 1 or desmoglein 3, resulting in the loss of cohesion between keratinocytes and subsequent skin blisters. 135 In 2011, Sachdevet et al 64 reported no association between PTPN22 C1858T and PV, confirming a previous observation in a Tunisian population. 136 A strong association between PTPN22 C1858T and two other autoimmune diseases has been reported.…”

“…Association between PTPN22 and other autoimmune diseases Besides the autoimmune diseases mentioned above, an association between PTPN22 and several other autoimmune diseases has been investigated, including ankylosing spondylitis (AS), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), idiopathic inflammatory myopathies (IIM), acute anterior uveitis (AAU), immune thrombocytopenia and pemphigus vulgaris (PV). 64,103,[127][128][129][130][131] The results are summarized in Supplementary Table S1. Only one case-control study was conducted for each disease in European populations or populations of European descent, making meta-analysis impossible.…”

“…49,[56][57][58][59][60][61][62][63][64][65][66][67] Americans of non-European descent showed a very low T allele frequency, as low as 1.1% in Mexico. 68 North Africa had a similar T allele frequency to Turkey and the Middle East, which ranged from 2 to 3.5%; [69][70][71][72][73][74][75] however, PTPN22 is not polymorphic in the black African population.…”

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population

“…Different HLA alleles have been reported in different populations, highlighting common HLA class II subtypes (especially between DR and DQ) in different ethnic groups. Currently, few non-HLA genes have been definitively linked to PV (Gazit et al, 2004;Javor et al, 2010;Sachdev et al, 2011;Tanasilovic et al, 2017); only a handful of studies on a limited number of genes in PV have been performed. The genome-wide association studies (GWASs) of PV in the Jewish population not only highlighted the role of HLA in the pathogenesis of PV but also identified the populationspecific non-HLA gene, ST18, as highly associated with the disease (Sarig et al, 2012;Vodo et al, 2016).…”

Region 1p13.2 including the RSBN1, PTPN22, AP4B1 and long non‐coding RNA genes does not bear risk factors for endemic pemphigus foliaceus (fogo selvagem)

“…Because the frequency of the rs2476601 T allele ( 1858T, 620Trp) was of only 1%–2% in Tunisians, the results did not permit exclusion of a possible effect of that PTPN22 variant on susceptibility to pemphigus in that population. Later, in a North American population, the frequency of the rs2476601 T allele was of 7.8% in both the pemphigus vulgaris patient and control samples, and no association was seen (Sachdev et al., ).…”