Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet beta cells and/or insulin resistance in liver, muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B (PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway, insulin secretion and autoreactive attack to pancreatic beta cells. Genetic mutation or overexpression of these phosphotases has been found to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B, a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model and PTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares more than 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substrates overlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP may have role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic beta cell apoptosis. The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutant have impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanism of R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. A receptor tyrosine phosphatase, PTPIA-2/beta is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/beta autoantibodies is valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2 are involved in type 2 diabetes via regulation of insulin production, beta cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulin response and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic and therapeutic strategies for diabetes.
Animals ; Diabetes Mellitus ; enzymology ; Diabetes Mellitus, Type 1 ; enzymology ; Diabetes Mellitus, Type 2 ; enzymology ; Humans ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; genetics ; metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 2 ; genetics ; metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics ; metabolism ; Protein Tyrosine Phosphatases, Non-Receptor ; classification ; genetics ; metabolism

OBJECTIVETo investigate the association of 1858C/T polymorphism of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) and rheumatoid arthritis (RA) susceptibility.

METHODSCMB, wanfang (Chinese) and PubMed databases were searched to get the studies on the association between 1858C/T polymorphism and RA susceptibility, and odds ratio (OR) and 95% confidential interval (CI) were calculated under different genetic models. Then heterogeneity, stratified analysis, and publication bias test were conducted in the study.

RESULTSA total of 32 studies (40 separate comparisons) with 25 059 RA patients and 25 466 controls were included in this meta-analysis. No evidence for publication bias was found in these studies. Meta-analysis showed an association between PTPN22 1858C/T polymorphism and RA (OR=1.606, 95%CI: 1.518-1.699, P<0.001). When stratified by ethnicity, T allele of PTPN22 1858C/T polymorphism was a risk allele in Caucasian (OR=1.612, 95%CI: 1.544-1.683, P<0.001); however, the polymorphism was not detected in Asians (or allele frequencies was extremely low). PTPN22 1858C/T polymorphism was associated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACCP).

CONCLUSIONT allele of PTPN22 1858C/T polymorphism is associated with RA susaptibility in Caucasians. PTPN22 1858C/T polymorphism is significantly more prevalent in RF-positive or ACCP-positive patients than in RF-negative or ACCP-negative patients.

Arthritis, Rheumatoid ; genetics ; European Continental Ancestry Group ; genetics ; Genetic Predisposition to Disease ; Humans ; Polymorphism, Single Nucleotide ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder that principally attacks flexible joints and synovia. The precise pathogenesis of RA remains unclear, and genetic factors probably play an important role in its etiology. In addition to genes from human leukocyte antigen (HLA) region, such as HLA-DRB, genes from non-HLA region, such as TIM-3, PTPN22, TRAF1/C5, STAT4, CCR5, PADI4 and FCGR2A may also contribute to its susceptibility. The advance in molecular genetics research on RA is reviewed here.
Arthritis, Rheumatoid ; genetics ; Exome ; Genetic Predisposition to Disease ; HLA-DRB1 Chains ; genetics ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Membrane Proteins ; genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics ; Receptors, IgG ; genetics

OBJECTIVETo study the expression level of peptidylarginine deiminase 4 (PADI4) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in the synovium of rat model of collagen-induced arthritis, and to explore their possible therapeutic role in rheumatoid arthritis.

METHODSThirty-two female Wistar rats weighing 100±20 g were randomly assigned into 3-week collagen-induced arthritis (CIA) model group (n=8), 4-week CIA model group (n=8), 6-week CIA model group (n=8), and the control group (n=8). The body weight changes of each group were recorded. The expression levels of PADI4 and PTPN22 were detected and compared by the methods of immunohistochemical staining and Western blot.

RESULTSArthritis of rat began to form 14 days after sensitization and the joint swelling reached peak at 28 days. The weights of the rats slowly grew both in CIA model groups and the control group. Immunohistochemical staining results showed that the positive expression of PADI4 and PTPN22 was mainly located in cartilage peripheral mononuclear cells, the cytoplasm of infiltrated cells, and bone marrow cavity. There were significant differences in the optical density of PADI4 and PTPN22 among CIA model groups and the control group (PADI4, 0.2898±0.012, 0.2982±0.022, 0.2974±0.031, 0.2530±0.013 in 3-week CIA model, 4-week CIA model, 6-week CIA model and control groups; PTPN22, 0.2723±0.004, 0.2781±0.010, 0.2767±0.008, 0.2422±0.019; all P <0.05). The expression bands of PADI4 were observed in Western blot 3 weeks after initial immunization, the thickest in the 4th week, and decreased in the 6th week. The expression bands of PTPN2 were observed at all the time points, with no obvious time-dependent trend.

CONCLUSIONSPADI4 and PTPN22 are obviously correlated with CIA in rat model. PADI4 is expressed at early stage of the disease, while the expression of PTPN22 sustains throughout the course.

Animals ; Arthritis, Experimental ; enzymology ; metabolism ; Blotting, Western ; Collagen ; administration & dosage ; Female ; Hydrolases ; metabolism ; Immunohistochemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; metabolism ; Protein-Arginine Deiminases ; Rats ; Rats, Wistar ; Synovial Membrane ; enzymology ; metabolism

OBJECTIVETo assess the association between genetic polymorphisms of 7 SNPs in PTPN22 and PADI4 genes and susceptibility to rheumatoid arthritis in Yunnan.

METHODSA case-control study was carried out on 192 patients of rheumatoid arthritis and 288 healthy controls. Genotypes of rs33996649 and 1858 loci within PTPN22 gene, and rs11203366 and rs874881 loci within PADI4 gene were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotypes of rs1635579, rs2428736 and rs2240340 in PADI4 gene were determined with pyrosequencing.

RESULTSThe frequencies of alleles and genotypes of rs2240340 locus in PADI4 gene showed a significant difference between rheumatoid arthritis and controls in Yunnan population (P U+003C 0.05).

CONCLUSIONOur results suggested that rs2240340 in PADI4 gene is associated with susceptibility to rheumatoid arthritis in Yunnan.

Alleles ; Arthritis, Rheumatoid ; genetics ; Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; China ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Hydrolases ; genetics ; Male ; Polymorphism, Single Nucleotide ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics ; Protein-Arginine Deiminases

OBJECTIVETo investigate the association between 1858C/T single nucleotide polymorphism on exon 14 of the protein tyrosine phosphatase nonreceptor-22 (PTPN22) gene and systemic lupus erythematosus in Chinese Han patients.

METHODSForty Chinese Han patients with SLE and 20 normal control subjects were enrolled in the study, and PTPN22 gene 1858 C/T polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTSNo significant difference was found in the CC, CT, and TT genotype frequencies or in the C and T allele frequencies between the SLE patients and the normal controls.

CONCLUSION1858C/T on PTPN22 gene might not be associated with the susceptibility of SLE in Chinese Han population.

Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; Child ; Exons ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Lupus Erythematosus, Systemic ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; genetics ; Young Adult

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals.
Autoimmunity ; Genes, Homeobox ; Genetics ; Genome-Wide Association Study* ; Graves Disease ; Hashimoto Disease ; Humans ; Leukocytes ; Neuregulin-1 ; Phenotype ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 ; Receptors, Interleukin-2 ; T-Lymphocytes, Cytotoxic ; Thyroid Diseases* ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyrotropin ; Thyroxine