Lymphoid Tyrosine Phosphatase Research Articles

Discovery of benzofuran-2-carboxylic acid derivatives as lymphoid tyrosine phosphatase (LYP) inhibitors for cancer immunotherapy

Lymphoid-tyrosine phosphatase (LYP) is mainly expressed in the immune system and plays an important role in the T-cell receptor (TCR) signaling pathway and tumor immunity. Herein, we identify benzofuran-2-carboxylic acid as a potent pTyr mimic and design a new series of new LYP inhibitors. The most active compound, D34 and D14, reversibly inhibits LYP (Ki = 0.93 μM and 1.34 μM) and possess a certain degree of selectivity toward other phosphatases. Meanwhile, D34 and D14 regulate the TCR signaling by specifically inhibiting LYP. In particular, D34 and D14 significantly suppress tumor growth in an MC38 syngeneic mouse model by boosting antitumor immunity, including activation of T-cell and inhibition of M2 macrophage polarization. Moreover, treatment of D34 or D14 upregulate PD-1/PD-L1 expression, which can be leveraged with PD-1/PD-L1 inhibition to augment immunotherapy. In summary, our study demonstrates the feasibility of targeting LYP for cancer immunotherapy and provides new lead compounds for further drug development.

Proautoimmune Allele of Tyrosine Phosphatase, PTPN22, Enhances Tumor Immunity.

The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein lymphoid tyrosine phosphatase) is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its proautoimmune allele have in tumor immunity is poorly defined. To interrogate the role this allele may have in the antitumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of lymphoid tyrosine phosphatase, PEST domain-enriched protein (PEP), is mutated at position 619 to produce the relevant proautoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wild-type mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cells and CD4 T cells. In addition, there are more conventional dendritic cell type 1 (cDC1) cells and fewer myeloid-derived suppressor cells in tumors from PEP-619WW mice. Interestingly, the tumor-infiltrating PEP-619WW cDC1 cells have decreased PD-L1 expression compared with cDC1 cells from PEP-wild-type mice. Taken together, our data show that the proautoimmune allele of Ptpn22 drives a strong antitumor response in innate and adaptive immune cells resulting in superior control of tumors.

Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation.

A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p < 0.05) and 3.6-fold (p < 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p < 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3- and anti-CD28-coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.

Role of Protein Tyrosine Phosphatase (PTPN22) Gene [C1858T] Functional Variant in Genetic Susceptibility of Psoriatic Arthritis in Kuwaiti Arabs

Background: Psoriatic arthritis (PsA) is a chronic, systemic inflammatory arthritic disease characterized by joint inflammation that is associated with cutaneous psoriasis, and can lead to pain, swelling, or stiffness in one or more joints. It results from a complex interplay between genetic, immunologic and environmental factors. A functional variant [C1858T] in the protein tyrosine phosphatase (PTPN22) gene, which encoded Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP) has been shown to be a negative regulator of T-cell activation. Objective: The objective of this study was to investigate an association between PTPN22 gene [C1858T] functional variant and PsA in Kuwaiti patients. Methods: We have investigated the association of PTPN22 gene functional variant in 102 Kuwaiti patients with psoriatic arthritis and compared it to that in 214 healthy controls. The genotypes for the PTPN22 gene [C1858T] variant were determined by using a PCR-RFLP method and confirmed by DNA sequence analysis. Results: The frequency of homozygous variant genotype (TT) was found to be significantly higher in PsA patients compared to that in the controls (p &lt;0.0001). Collectively, the variant genotype was detected in homozygous and heterozygous combinations in 30% patients (p &lt;0.0001) compared to 16% in the controls. The frequency of variant genotype was found to be highest in the early-onset PsA patients (age &gt;25-34y). No correlation was detected between the variant genotype (TT) and gender in the Kuwaiti PsA patients. Conclusion: Our data show a significant association of PTPN22 gene functional variant [C1958T] with PsA in Kuwaiti patients and highlight its role in determining the genetic susceptibility along with other factors.

Identification of novel thiourea‐stilbene‐triazine conjugates as persuasive lymphoid tyrosine phosphatase inhibitors

AbstractA library of novel thiourea‐based symmetrical stilbene‐triazines (5a‐i) was synthesized in an effort to develop new protein tyrosine phosphatase LYP inhibitors. The versatile nature of 2,4,6‐trichloro‐1,3,5‐triazine allows considerable scope for derivatization and hence exploration of structure activity relationships. A convenient and versatile three‐step synthetic approach involved the successive replacement of the two chloro groups of 2,4,6‐trichloro‐1,3,5‐triazine by a variety of substituents for structural modification. The newly synthesized derivatives were subjected to tyrosine phosphatase LYP inhibition studies. The results for the in vitro bioassays were promising with the identification of compound 5k and 5l having a 4‐methyl and 4‐methoxy substituent on phenyl ring, as the lead and selective candidate for LYP inhibition with an IC50 value of 2.1 ± 0.05 μM and 28 ± 3.3 μM, respectively. Moreover, docking studies were carried out to determine the possible interaction sites of thiourea‐based stilbene‐triazine compounds with Lymphoid Tyrosine Phosphatase. Results of docking computations further ascertained the inhibitory potential of compound 5k and 5l. The results indicated that the compound 5k may serve as a structural model for the design of most potent LYP inhibitors.

Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?

Autoimmune thyroid disease (AITD) and type 1 diabetes mellitus (T1DM) are two common autoimmune diseases that can occur concomitantly. In general, patients with diabetes have a high risk of AITD. It has been proposed that a complex genetic basis together with multiple nongenetic factors make a variable contribution to the pathogenesis of T1DM and AITD. In this paper, we summarize current knowledge in the field regarding potential pathogenic factors of T1DM and AITD, including human leukocyte antigen, autoimmune regulator, lymphoid protein tyrosine phosphatase, forkhead box protein P3, cytotoxic T lymphocyte-associated antigen, infection, vitamin D deficiency, and chemokine (C-X-C motif) ligand. These findings offer an insight into future immunotherapy for autoimmune diseases.

Role of C1858T Polymorphism of Lymphoid Tyrosine Phosphatase in Egyptian Children and Adolescents with Type 1 Diabetes.

Type 1 Diabetes Mellitus (T1DM) is a multifactorial autoimmune disease. The Protein Tyrosine Phosphatase Non-receptor 22 (PTPN22) gene is an important negative regulator of signal transduction through the T-cell Receptors (TCR). A PTPN22 polymorphism, C1858T, has been found to be a risk determinant for several autoimmune diseases, including T1DM, in different populations. The present study was aimed to analyze a possible association between the C1858T polymorphism in Egyptian children with T1DM. This case-control study included 240 children divided evenly between T1DM patients and controls. The PTPN22 C1858T polymorphism was genotyped using polymerase chain reaction with Restriction Fragment Length Polymorphism (RFLP). Both the 1858CΤ and 1858ΤΤ genotypes and the 1858T allele were found more frequently in patients (32.5% and 18.7%, respectively) than in controls (10% and 5.0%, respectively), P=0.013 and P=0.007, respectively. Among females, the 1858T allele was more common in patients (18%) than in controls (2.6%), P=0.014. These findings suggest that the PTPN22 1858T allele could be a T1DM susceptibility factor in the Egyptian population and that it might play a different role in susceptibility to T1DM according to gender in T1DM patients.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene polymorphisms in liver transplant donors and impact on acute cellular liver transplant rejection.

The PTPN22 gene encodes the lymphoid protein tyrosine phosphatase involved in regulation the immune response. The single nucleotide polymorphisms (SNPs) rs1217388, rs1310182, rs2476601, and rs2488457 are located within the PTPN22 gene. We investigated whether these SNPs in liver transplant donors are associated with acute cellular rejection in the recipients. The SNPs were analyzed in donors (n = 104) of recipients who did not develop an acute cellular rejection and in donors (n = 53) of corresponding recipients developing an acute cellular rejection. No significant differences in genotype and allele frequencies of these SNPs were detected in either of the group. Our data suggest that these SNPs in liver transplant donors have no impact on the susceptibility of acute cellular liver transplant rejection.

Pro-autoimmune genetic risk variant, PTPN22 1858C&amp;gt;T accelerates formation of tertiary lymphoid structures in a mouse model of Type 1 Diabetes

Abstract Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes a lymphoid tyrosine phosphatase adaptor molecule involved in many biological pathways. Studies have shown an association with the minor allelic variant of PTPN22, R620W, and increased incidence of numerous autoimmune disorders, including type 1 diabetes (T1D). The exact mechanisms by which this pro-autoimmune risk allele enhances the incidence of T1D is unknown. To examine the immunological pathways altered by this risk variant, our lab introduced the murine ortholog of the human R620W allele, R619W, into the endogenous locus of Non-obese diabetic (NOD) mice that develop spontaneous T1D. NOD mice harboring this mutation (NOD 619W/W) demonstrated a similar phenotype seen in affected humans with accelerated onset of T1D and enhanced anti-islet autoantibodies (IAA). Preliminary data generated in our lab show enhanced islet infiltration in the pancreata of NOD 619 W/W compared to wild type NOD mice starting at 4–5 weeks of age. Studies have shown that infiltrating lymphocytes can organize into tertiary lymphoid structures (TLS) at the insulitis lesions of pre-diabetic mice. In addition to enhanced infiltration, NOD 619W/W pancreata also show characteristics of TLO formation at the sites of insulitis. Studies have shown that TLOs contribute to disease manifestation and prevention of TLO formation in the pancreas can prevent pathogenesis. Therefore, we are actively examining the immune cell types and pathways altered by the PTPN22 risk allele that may enhance early islet infiltration and promote the formation of TLOs in the pancreata of NOD 619 W/W hosts.

Analysis of the rs2476601 polymorphism of PTPN22 in Mexican mestizo patients with leprosy.

Leprosy, a human chronic granulomatous disease caused by Mycobacterium leprae (M. leprae), remains endemic in certain countries despite the use of multidrug therapy. Recently, several host genes modulating the immune responses to M. leprae infection have been suggested to influence the acquisition and clinical course of leprosy. Lymphoid protein tyrosine phosphatase, encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, serves a negative regulatory role in T cell activation. The non-synonymous single-nucleotide polymorphism (SNP) rs2476601 (1858C>T) has been associated with autoimmune diseases. Here, the present study investigated if rs2476601 polymorphism was associated with leprosy in a Mexican mestizo population. Genotyping was performed in patients with leprosy (n=189) and control subjects (n=231) from regions with higher incidence of leprosy. Genotypic (P=0.44) and allelic frequencies (P=0.45) of the rs2476601 polymorphism were similar between patients and controls; genotypic frequencies were 91 vs. 94% for CC and 9 vs. 6% for CT, and the TT genotype was absent in both groups. Allelic frequencies were 96 vs. 97% for C, and 4 vs. 3% for T. In the same way, the genotypic (P=0.46) and allelic frequencies (P=0.47) from MB patients and controls were similar. In conclusion, there was a lack of association of the PTPN22 rs2476601 polymorphism with the development of leprosy, which suggests that this SNP was not a genetic risk factor for leprosy in the Mexican mestizo population studied.

Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes

In autoimmune diseases as Type 1 diabetes, the actual treatment that provides the missing hormones is not able, however, to interrupt the underlining immunological mechanism. Importantly, novel immunotherapies are exploited to protect and rescue the remaining hormone producing cells. Among probable targets of immunotherapy, the C1858T mutation in the PTPN22 gene, which encodes for the lymphoid tyrosine phosphatase (Lyp) variant R620W, reveals an autoimmunity related pathophysiological role. Our scope was to establish new C1858T PTPN22 siRNA duplexes delivered by liposomal carriers (lipoplexes) to patients’ PBMC. Following lipoplexes treatment, CD3+ and CD3− immunotypes were efficiently transfected; cell integrity and viability were preserved. Specific target mRNA down-modulation was observed. After T cell receptor stimulation, in lipoplexes-treated PBMC Lyp function was restored by increased release of IL-2 in cultures. Results set-up the stage for ultimate trials in the treatment of autoimmunity based on the specific inhibitory targeting of C1858T PTPN22 by lipoplexes.

Identification of immunological pathways altered by a pro-autoimmune genetic risk variant, PTPN22 1858C&amp;gt;T, that enhances the prevalence of Type 1 diabetes

Abstract Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) encodes lymphoid tyrosine phosphatase (Lyp) adaptor molecule that is involved in numerous biochemical pathways in hematopoietic cells. Studies have shown an association with the minor allelic variant of PTPN22, R620W, and increased incidence of autoimmune disorders such as type 1 diabetes (T1D). Approximately 10% of the North American population carry the R620W minor allele, which increases the risk of T1D by as much as 2–4-fold. The exact mechanisms by which this pro-autoimmune risk allele enhances the incidence of T1D is unknown. To address this gap of knowledge our lab introduced the murine ortholog of the human R620W allele, R619W, into the endogenous locus of Non-obese diabetic (NOD) mice that develop spontaneous T1D. NOD mice harboring this mutation (NOD 619W/W) demonstrated a similar phenotype seen in affected humans with accelerated onset of T1D and enhanced anti-islet autoantibodies (IAA). Clinical manifestation of T1D in humans is preceded by IAA in the serum. IAA affinity can often identify individuals at risk of developing diabetes. Germinal centers (GC) are lymphoid structures where affinity maturation occurs with the help of follicular helper T cells (Tfh) cells. An increase in circulating Tfh cells has been reported in newly diagnosed and pre-diabetic individuals, thus suggesting a role for GC reactivity in T1D. Similar to human observations, NOD 619W/W mice also show enhanced IAA and increased Tfh and GC B cell numbers before onset of T1D therefore, our lab is currently examining the immunological pathways altered by this pro-autoimmune risk alleles and their contributions to T1D.

Association Study of the PTPN22 Gene Polymorphisms with Systemic Lupus Erythematosus in Lorestan Province of Iran

Background: The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene encodes the lymphoid protein tyrosine phosphatase. Recent studies demonstrated the association between the +1858C > T, -1123G > C variants of PTPN22 gene, and different autoimmune diseases. The current study aimed at examining the association between the polymorphism of PTPN22 gene and systemic lupus erythematosus (SLE) in the Southwest of Iran. Methods: The current study included 120 patients with SLE and 120 healthy volunteers as a control group. Genomic DNA was extracted and the genotyping was performed based on the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Results: Frequency of 1858T allele (P < 0.001, OR = 0.44, 95% CI = 0.291 to 0.663)showed association and frequency of 1123C allele (P = 0.307, OR = 0.811, 95% CI = 0.543 to 1.212)showed no association with SLE in patients compared with the control group in the studied population. Conclusions: Statistical analysis showed no relationship among gender, genotype, and SLE risk. However, there was a significant relationship between age and the SLE risk (P = 0.006).

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes.

Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with paradoxical reduced T cell activation, may represent a valid therapeutic target. We aimed to develop novel wild type PTPN22 short interfering RNA duplexes (siRNA) and optimize their delivery into Jurkat T cells and PBMC by using liposomal carriers. Conformational stability, size and polydispersion of siRNA in lipoplexes was measured by CD spectroscopy and DLS. Lipoplexes internalization and toxicity evaluation was assessed by confocal microscopy and flow cytometry analysis. Their effect on Lyp expression was evaluated by means of Western Blot and confocal microscopy. Functional assays through engagement of TCR signaling were established to evaluate biological consequences of down-modulation. Both Jurkat T cells and PBMC were efficiently transfected by stable custom lipoplexes. Jurkat T cell morphology and proliferation was not affected. Lipoplexes incorporation was visualized in CD3+ but also in CD3- peripheral blood immunotypes without signs of toxicity, damage or apoptosis. Efficacy in affecting Lyp protein expression was demonstrated in both transfected Jurkat T cells and PBMC. Moreover, impairment of Lyp inhibitory activity was revealed by increase of IL-2 secretion in culture supernatants of PBMC following anti-CD3/CD28 T cell receptor-driven stimulation. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on the selective inhibition of variant PTPN22 allele using lipoplexes of siRNA antisense oligomers.

New Substituted 1‐Aryl‐4,4,6‐Trimethyl‐3,4‐Dihydropyrimidine‐2‐(1H)Thiones; A Metal‐Free and Solvent‐Free Synthesis, Characterization, and Lymphoid Tyrosine Phosphatase Inhibition Studies

A series of fourteen 3,4‐dihydropyrimidine‐2‐thiones (3a–n) were synthesized by a green protocol, and their structures were characterized by spectroanalytical data. The compounds were obtained in high yields by efficient annulation of mesityl oxide (4‐methylpent‐3‐en‐2‐one) with anilines in the presence of potassium thiocyanate. The reaction is essentially metal‐catalyst‐ and solvent‐free, as mesityl oxide itself is the solvent as well as the reactant. The compounds were tested for their ability to inhibit the lymphoid tyrosine phosphatase PTPN22, and 5 of the 14 compounds exhibited IC50 values in the mid‐micromolar range, with the most potent hit being the compound 3d, having a methoxy substituent at the 2‐position of the phenyl ring with an IC50 = 18 ± 1 μM, and second most potent compound (3c) with an IC50 value of 45 ± 3 μM, having methyl substituents at both 2‐ and 4‐position of the phenyl ring.

Association of PTPN22 Haplotypes (-1123G>C/+1858C>T) with Rheumatoid Arthritis in Western Mexican Population.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP), a consequence of the breakdown of immune tolerance. The lymphoid tyrosine phosphatase (Lyp) protein has significant effects on maintenance of peripheral immune tolerance. Two polymorphic variants (−1123G>C and +1858C>T) at PTPN22 gene that encodes this protein have been associated with autoimmune disorders and found in strong linkage disequilibrium in Caucasian population. We evaluated whether PTPN22 haplotypes (−1123G>C/+1858C>T) are associated with anti-CCP antibodies, as well as susceptibility to RA in a Western Mexican population. A total of 315 RA patients and 315 control subjects (CS) were included. The polymorphisms were genotyped by PCR-RFLP and the anti-CCP antibodies were determined by ELISA. The PTPN22 polymorphisms were in strong linkage disequilibrium (D′ = 1.00 in CS). The susceptibility haplotype CT was significantly more frequent in RA patients than in CS (OR 2.18, 95% CI 1.15–4.16, p = 0.01). No association between haplotypes and anti-CCP antibodies levels was observed. In conclusion, this study confirmed that −1123G>C and +1858C>T PTPN22 polymorphisms are in strong linkage disequilibrium and the CT haplotype is a susceptibility marker to RA in Western Mexico. However, the PTPN22 haplotypes are not associated with anti-CCP antibodies.

Association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism and susceptibility to vitiligo: Systematic review and meta-analysis.

Protein tyrosine phosphatase, non-receptor type 22 gene, which translates to lymphoid tyrosine phosphatase, is considered to be a susceptibility gene marker associated with several autoimmune diseases. Several studies have demonstrated the association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism with vitiligo. However, these studies showed conflicting results. Meta-analysis of the same was conducted earlier that included fewer number of publications in their study. We performed a meta-analysis of a total of seven studies consisting of 2094 cases and 3613 controls to evaluate the possible association of protein tyrosine phosphatase, non-receptor type 22 +1858C>T polymorphism with vitiligo susceptibility. We conducted a literature search in PubMed, Google Scholar and Dogpile for all published paper on protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism and vitiligo risk till June 2016. Data analysis was performed by RevMan 5.3 and comprehensive meta-analysis v3.0 software. Meta-analysis showed an overall significant association of protein tyrosine phosphatase, non- receptor type 22 +1858C→T polymorphism with vitiligo in all models (allelic model [T vs. C]: odds ratio = 1.50, 95% confidence interval [1.32-1.71], P< 0.001; dominant model [TT + CT vs. CC]: odds ratio = 1.61, 95% confidence interval [1.16-2.24], P = 0.004; recessive model [TT vs. CT + CC]: odds ratio = 4.82, 95% confidence interval [1.11-20.92], P = 0.04; homozygous model [TT vs. CC]: odds ratio = 5.34, 95% confidence interval [1.23-23.24], P = 0.03; co-dominant model [CT vs. CC]: odds ratio = 1.52, 95% confidence interval [1.09-2.13], P = 0.01). No publication bias was detected in the funnel plot study. Limited ethnic-based studies, unable to satisfy data by gender or vitiligo-type are some limitations of the present meta-analysis. Stratifying data by ethnicity showed an association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T with vitiligo in European population (odds ratio = 1.53, 95% confidence interval [1.34-1.75], P< 0.001) but not in Asian population (odds ratio = 0.59, 95% confidence interval [0.26-1.32], P = 0.2). In conclusion, protein tyrosine phosphatase, non-receptor type 22 +1858 T allele predisposes European individuals to vitiligo.

PTPN22 R620W minor allele is a genetic risk factor for giant cell arteritis

Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although...

The functional PTPN22 C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico.

Rheumatoid arthritis (RA) is a complex genetic disease. Human leukocyte antigen (HLA) and non-HLA genes are reportedly associated with an increased risk of RA. The protein tyrosine phosphatase non-receptor 22 gene (PTPN22), which encodes the lymphoid tyrosine phosphatase (LYP) protein, is one of the best examples of a non-HLA gene associated with a risk for RA in several populations. The functional PTPN22 C1858T (R620W) non-synonymous polymorphism is widely associated with an increased risk for RA in Europeans and non-Europeans. The aim of this study was to determine if the PTPN22 C1858T polymorphism confers susceptibility to RA in a sample of patients from Mexico. This study included 364 RA patients and 387 non-related controls from Central Mexico. Genotyping of the PTPN22 C1858T (rs2476601) polymorphism was performed using allelic discrimination assays with TaqMan probes. The functional PTPN22 C1858T polymorphism was associated with an increased risk for RA in our study population. The CC vs CT genotype in RA patients versus healthy controls had an odds ratio (OR) of 4.17 (95% CI 1.79-9.74, p = 0.00036), while T allele had an OR of 4.06 (95% CI 1.75-9.41, p = 0.00043). PTPN22 is a genetic risk factor for developing RA in the Mexican population.

Assessment of biochemical parameters and characterization of TNFα -308G/A and PTPN22 +1858C/T gene polymorphisms in the risk of obesity in adolescents.

Obesity is currently considered an inflammatory condition associated with autoimmune diseases, suggesting a common origin. Among other factors, candidate genes may explain the development of this disease. Polymorphisms in the tumor necrosis factor α (TNFα) and lymphoid protein tyrosine phosphatase (PTPN22) genes lead to an increased risk to development of immune and inflammatory diseases. The aim of the present study was to analyze the biochemical parameters and the effect of the TNFα -308G/A and PTPN22 +1858C/T polymorphisms in the susceptibility of adolescents to obesity. A group of 253 adolescent subjects were recruited and classified as obese, overweight or normal weight according to their nutritional status. Anthropometric measurements, clinical and biochemical data were analyzed. DNA was extracted from peripheral blood samples by the phenol-chloroform method, and TNFα -308G/A and PTPN22 1858C/T polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism assays. Clinical, genetic and biochemical parameters were analyzed to determine the existence of a possible association with the development of obesity. Statistically significant differences in body mass index, insulin, triglyceride levels and homeostatic model assessment for insulin resistance (HOMA-IR) index were observed among the three groups analyzed (P≤0.05). The studied polymorphisms did not confer a risk for developing obesity in the analyzed population (P>0.05); however, significantly low levels of insulin and decreased rates of HOMA-IR were observed in the 1858 CT genotype carriers of the PTPN22 gene. In conclusion, no association between the TNFα -308G/A and PTPN22 +1858C/T polymorphisms and the risk to development of obesity in the adolescent population analyzed was observed. However, the 1858 CT genotype of the PTPN22 gene was associated with variations of certain biochemical parameters analyzed.