Sex-specific association of the human PTPN22 1858T-allele with type 1 diabetes

Type 1 diabetes (T1D) is a common organ-specific autoimmune disease of complex aetiology, involving the interaction of a large number of disease-associated genes. By comparison of a Danish population sample of 253 Caucasian children and adolescents with T1D and a control group consisted of 354 unrelated healthy blood donors, the present study provides evidence of an isolated association of the disease-associated PTPN22 1858T-allele with T1D to the female sex. Furthermore, the present data suggest that PTPN22 genotypes affect the age of onset in a sex-specific manner. The increased frequency of the risk allele and its association with age at onset in female T1D children and adolescents indicates that the genetic contribution to disease pathogenesis is more prominent in females in this population of Danish patients.     

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.     

ORIGINAL ARTICLE: PTPN22 C1858T Polymorphism in Women with Endometriosis

Citation Gomes FMCS, Bianco B, Teles JS, Christofolini DM, de Souza AMB, Guedes AD, Barbosa CP. PTPN22 C1858T polymorphismin women with endometriosis. Am J Reprod Immunol 2010; 63: 227–232 Problem Endometriosis has been suggested to be an autoimmune disease and recently, an allelic variation of the PTPN22 (C1858T) gene was revealed to be associated with the development of autoimmunity. The aim of the study was to determine the frequency of the PTPN22 (C1858T) polymorphism in Brazilian women with endometriosis as compared with controls. Method of study Case–control study included 140 women with endometriosis and a control group consisting of 180 healthy fertile women without a history of endometriosis and/or autoimmune diseases from the ABC School of Medicine. The PTPN22 (C1858T) polymorphism was studied by restriction fragment length polymorphism polymerase chain reaction (RFLP‐PCR). Results Genotypes CC, CT and TT of PTPN22 polymorphism presented frequencies of 67.9, 30.0 and 2.1% in the women with endometriosis (P = 0.008); 76.2, 19.0 and 4.8% in women with minimal/mild endometriosis (P = 0.173); 61.0, 39.0 and 0.0% in women with moderate/severe endometriosis (P ≤ 0.001) and 82.8, 16.1 and 1.1% in control group. Allele C and T were present in 82.9 and 17.1%; 85.7 and 14.3%; 80.5 and 19.5%; and 90.8 and 9.2% respectively, in women with endometriosis (P = 0.004), women with minimal/mild endometriosis (P = 0.148), women with moderate/severe endometriosis (P = 0.002) and control group. Conclusion The data suggest that in Brazilian women polymorphism PTPN22 (C1858T) may be an important genetic predisposing factor for endometriosis, especially, in advanced disease.     

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

A functional single nucleotide polymorphism (SNP) C1858T in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encoding an intracellular phosphatase with negative regulatory effects on T-cell activation is associated with some autoimmune diseases in Caucasians. Taking into account firstly, that SNP frequencies may vary across populations and, secondly, that replication studies are important to confirm previous associations, we examined the influence of PTPN22 polymorphism in 621 Colombian patients with four autoimmune diseases. Accordingly, 298 patients with rheumatoid arthritis (RA), 143 with systemic lupus erythematosus (SLE), 70 with primary Sjogren's syndrome (pSS) and 110 with Type 1 diabetes (T1D) were studied. The control group consisted of 308 matched healthy individuals. Genotyping of PTPN22 was performed by the real-time polymerase chain reaction technology, using the Taq Man 5'-allele discrimination assay. The 1858 T allele was found to be a risk factor for pSS (odds ratio (OR)=2.42), SLE (OR=2.56), and T1D (OR=1.83). A lower but nonsignificant trend was observed for RA (OR=1.26). These results confirm the influence of PTPN22 in autoimmunity and indicate that autoimmune phenotypes could represent pleiotropic outcomes of nonspecific disease genes that underlie similar immunogenetic mechanisms.     

C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition

Recent findings have demonstrated that the single nucleotide polymorphism 1858C-->T located at the P1 motif of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene has functional relevance and is associated with a variety of autoimmune diseases. The aim of this study was to assess the role of the PTPN22 1858C-->T polymorphism in the genetic predisposition to celiac disease (CD). We analyzed a case-control cohort composed by 534 patients with CD and 653 healthy controls and additionally a panel of 271 celiac families. The PTPN22 1858C-->T genotyping was performed by TaqMan 5' allelic discrimination assay. We did not observed any statistically significant deviation after comparing allele and genotypic frequencies of PTPN22 1858C-->T between patients with CD and controls. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of PTPN22 1858C-->T alleles to the affected offspring. Therefore, our data suggest that the PTPN22 1858 single nucleotide polymorphism has no, or only a negligible, effect on CD susceptibility in this Spanish population.     

The PTPN22 1858T variant is not associated with primary biliary cirrhosis

The minor allele of a single nucleotide polymorphism (SNP) in the PTPN22 gene (1858T) encoding the Lyp-tyrosine phosphatase has been recently associated with multiple autoimmune disorders, raising the possibility that this variant may also represent a risk allele for primary biliary cirrhosis (PBC). We therefore investigated the possible association of the PTPN22(1858T) variant with PBC in a Canadian population. We studied 160 Caucasian patients with biopsy and antimitochondrial antibodies (AMA)-proven PBC who were genotyped for the PTPN22(C1858T) SNP using a single-base primer extension assay and mass spectrometry. The frequency of the PTPN22(1858T) allele was then compared between the patients and 290 healthy controls. No association was detected between the PTPN22(1858T) allele and PBC, the frequency of this variant being similar in patients with PBC (7.5%) and controls (8.4%). Restricting the analysis to patients with PBC with any second autoimmune condition or specifically with sicca syndrome or autoimmune thyroid disease also revealed no association with this variant. Thus the PTPN22(1858T) variant is not associated with PBC or with the combination of PBC and a second autoimmune disease. These data suggest that this variant does not confer risk for PBC and does not account for the frequent presence of other autoimmune diseases in patients with PBC.     

Association of PTPN22 C1858T polymorphism and type 1 diabetes: a meta-analysis

Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identified as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a fixed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859～2.041, P < 0.001). After stratification by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was significantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852~2.045, P < 0.001; OR = 1.946, 95% CI = 1.690~2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations.     

Association study of PTPN22 C1858T polymorphism in Trypanosoma cruzi infection

In this study we investigated a possible role for the single nucleotide polymorphism C1858T of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene in determining the susceptibility to Trypanosoma cruzi infection, as well as in development of chagasic heart disease. This study included 316 patients with Chagas' disease and 520 healthy individuals from Colombia and Peru. Genotyping of PTPN22 was performed by the real-time polymerase chain reaction technology, using the TaqMan 5' allelic discrimination assay. No statistically significant differences in the frequency of PTPN22 C1858T gene polymorphism between chagasic patients and controls or between asymptomatic and cardiomyopathic individuals were observed. Our findings suggest that the PTPN22 polymorphism analyzed does not play a major role in the development of Chagas' disease in the Colombian and Peruvian populations.     

Mutation screening of the PTPN11 gene in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden death. It is an autosomal dominant disorder predominantly caused by mutations in genes encoding for sarcomeric proteins. Only 50-60% of HCM probands have mutations in known genes suggesting the presence of additional disease genes. Noonan and LEOPARD syndromes are characterised by multiple dysmorphia and cardiac defects with HCM present in approximately 20% of cases. Both syndromes are caused by mutations in the PTPN11 gene which codes for the protein tyrosine phosphatase SHP-2. It is suspected but unproven that the cardiac phenotype may predominate or even be present in isolation. In order to determine possible involvement of this gene in the pathogenesis of HCM, we performed mutation screening of the PTPN11 coding region in 250 selected HCM probands (200 patients without mutations in sarcomeric genes and 50 with identified mutations). No mutations in PTPN11 were identified. Our data suggests that mutations in the PTPN11 gene are not a cause of HCM in the absence of Noonan/LEOPARD syndromes.     

Association of PTPN22 C1858T Polymorphism and Type 1 Diabetes: A Meta-analysis

Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identi?ed as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a ?xed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859～2.041, P < 0.001). After strati?cation by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was signi?cantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852～2.045, P < 0.001; OR = 1.946, 95% CI = 1.690～2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations.     

Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.     

A case-control study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn's disease

In Crohn's disease (CD), the whole gastrointestinal tract can be affected by discontinuous and transmural inflammation. The terminal ileum and colon are especially prone to inflammation that comprises granulomata and later intestinal and perianal fistulas. Genome-wide linkage and epidemiological studies established genetic predisposition factors to CD. Recently, a variation of the intracellular protein tyrosine phosphatase nonreceptor-type 22 (PTPN22) was associated with several autoimmune diseases. Here, we analysed the functionally relevant polymorphism R620W (rs 2476601) of the PTPN22 gene in 146 patients suffering from CD using restriction fragment length polymorphism (RFLP) analyses. This study revealed evidence that PTPN22 variation may have no influence in the genetic predisposition to CD, at least not in another well-characterized Caucasian cohort.     

类风湿性关节炎相关基因PTPN22 C1858T在中国6个民族中的遗传多态性研究

目的 研究与类风湿性关节炎相关的PTPN22 C1858T在中国蒙古族、满族、达斡尔族、哈萨克族、回族和四川汉族6 个人群中的遗传多态性。方法 应用PCR-RFLP方法检测6 个人群共539个个体中PTPN22 1858T等位基因频率。结果 6个人群中PTPN22 1858T等位基因频率是0.0195（n=539）分布符合Hardy-Weinberg平衡;在蒙古族、满族、达斡尔族、哈萨克族、回族和四川汉族人群中PTPN22 1858T等位基因频率分别是0.0114、0.0143、0、0.0698、0.0216和0且6个人群间差异有统计学意义（P<0.05）。结论 获得了中国6 个人群PTPN22 1858T等位基因频率数据,为评估中国不同人群对类风湿性关节炎的遗传易感性及流行病学研究提供了基本的数据。     

Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis

Background  

The genetic contribution to the aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not well defined. Across different autoimmune diseases some genes with immunomodulatory roles, such as PTPN22, are frequently associated with multiple diseases, whereas specific HLA associations, such as HLA-B27, tend to be disease restricted. We studied ten candidate loci on the basis of their immunoregulatory role and prior associations with type 1 diabetes (T1D). These included PTPN22, CTLA4 and CD226, which have previously been associated with AAV.     

Association of PTPN22+1858C/T polymorphism with Type 1 diabetes in the North Indian population

A nonsynonymous SNP +1858C/T (rs2476601) in the protein tyrosine phosphatase, nonreceptor type 22(PTPN22) gene leading to Arg 620 Trp substitution is known to be associated with susceptibility to type 1 diabetes (T1D) and several other autoimmune diseases. We studied this polymorphism in 145 T1D patients and 210 healthy controls from North India. The minor allele +1858T was observed to be significantly increased among patients as compared to healthy controls (2.76% vs 0.5%, P = 0.027, OR = 5.93; 95% CI = 1.4–24.8). The association was also observed at the level of heterozygous C/T genotype (5.5% vs 0.95%, P = 0.026, OR = 6.07; 95% CI = 1.43–25.6). The T allele and C/T genotype were predominantly found among patients who were positive for both glutamic acid decarboxylase 65 (GAD65) and insulin antigen 2 (IA2) autoantibodies and showed significantly increased frequencies (10%, P = 0.034, OR = 11.67; 95% CI = 1.58–84.1 and 20%, P = 0.031, OR = 13.0; 95% CI = 1.66–97.5, respectively) as compared to patients negative for these autoantibodies (0.95% and 1.9%, respectively). The results suggest that the PTPN22+1858T allele is positively associated with T1D in the North Indian population.     

PTPN22基因多态性与Graves病

弥漫性甲状腺亢进Graves病1是一种多因素引起的疾病,遗传易感性在其发病中起到重要的作用。蛋白酪氨酸磷酸酶非受体型122（protein tyrosine phosphatase non—receptortype22,PTPN22）基因作为其多种自身免疫性疾病的易感基因,被认为通过编码淋巴酪氨酸磷酸酶,在T细胞信号转导中起负性调节作用,可维持免疫系统平衡。而PTPN22的C1858T基因多态性,会使T细胞表面受体的信号减弱和调节性T细胞出现功能缺陷,从而引起Graves病的发生。     

The PTPN22 promoter polymorphism -1123G>C association cannot be distinguished from the 1858C>T association in a Norwegian rheumatoid arthritis material

The protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene has, during the last 2 years, been recognized as a susceptibility gene for numerous autoimmune diseases, including rheumatoid arthritis (RA) and type 1 diabetes. An association between the exonic 1858C>T single nucleotide polymorphism (SNP) and RA has repeatedly been replicated in several Caucasian populations. The SNP is not associated with autoimmune diseases in Asian populations, as the 1858T allele is almost absent. Recently, a promoter polymorphism -1123G>C was proposed to be associated with acute-onset type 1 diabetes in Japanese and Korean populations. Furthermore, in Caucasian populations, the presence of additional PTPN22 risk variants has been suggested, indicating that the 1858C>T risk variant cannot explain the entire disease association observed in the region. In this study, we wanted to jointly address and integrate these separate findings to further elucidate the association between the PTPN22 gene and RA in a Norwegian material of 861 RA patients and 559 healthy controls. Our results revealed that the strength of the association with the PTPN22 promoter polymorphism, -1123G>C, is analogous to that observed for 1858C>T. As the -1123G>C variant is also polymorphic in Asian populations, our data underpin the need to further explore the association between this variant and autoimmune diseases in different populations.     

Association between PTPN22 C1858T and type 1 diabetes: a replication in continental Italy

The missense PTPN22 C1858T polymorphism recently emerged as an important population-independent risk factor for type 1 diabetes (T1D) and other autoimmune diseases. The PTPN22 gene encodes the lymphoid tyrosine phosphatase (LYP), a negative regulator of signal transduction through the T-cell receptor. Although the frequency of the polymorphism is variable among different ethnic groups, the association between PTPN22 *T1858 and T1D has been replicated in several populations. Here, we contribute the first replication of the association between PTPN22 and T1D in populations from continental Italy, carried out in two independent samples of T1D patients ( N  = 216 and 82) and controls ( N  = 271 and 89). Our data also suggest that T1D carriers of the *T1858 allele could be at increased risk for other comorbid autoimmune disorders.     

Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population

Background

The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population.

Methods

A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System.

Results

We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed.

Conclusion

Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.     

The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity

Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these diseases.An increasing amount of epidemiologic investigations has associated the presence of the C1858T polymorphism in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene to the onset of several autoimmune diseases including insulin-dependent diabetes mellitus (Type 1 diabetes).PTPN22 encodes for the lymphoid tyrosine phosphatase Lyp. This belongs to non-receptor-type protein tyrosine phosphatases involved in lymphocyte activation and differentiation. In humans, Lyp may have a role in the negative regulation of T cell receptor signaling. The single nucleotide polymorphism C1858T encodes for a more active phosphatase Lyp R620W. This has the ability to induce a higher negative regulation of T cell receptor signaling. Thus, C1858T could play an important role at the level of thymocyte polarization and escape of autoreactive T lymphocytes, through the positive selection of otherwise negatively selected autoimmune T cells.In this review we discuss the physiological role exerted by the PTPN22 gene and its encoded Lyp product in lymphocyte processes. We highlight the pathogenic significance of the C1858T PTPN22 polymorphism in human autoimmunity with special reference to Type 1 diabetes.Recently the genetic variation in PTPN22 was shown to induce altered function of T and B-lymphocytes. In particular BCR signaling defects and alterations in the B cell compartment were reported in T1D patients. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity aiming to selectively target the variant Lyp protein in autoreactive T and B lymphocytes.