Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modeling the effect of PTPN22 in rheumatoid arthritis.

ABSTRACT: In order to model the effect of PTPN22 on rheumatoid arthritis (RA), we determined the combination of single-nucleotide-polymorphisms (SNPs) showing the strongest association with RA. Three SNPs (rs2476601-rs12730735-rs11102685) were selected for which we estimated the genotypic relative risks (GRRs) of the corresponding genotypes. On the basis of these GRRs we defined four at-risk genotypic classes. Relative to the class of reference risk, individuals had a risk approximately multiplied by two, three, or four. This classification was confirmed by the excess of identity-by-descent (IBD) sharing (IBD = 2) for the sibs of an index in the high-risk class and by excess of non-IBD sharing (IBD = 0) when the index belonged to the low-risk class. The observed data could not be explained by the role of a single variant but were compatible either with a joint effect of the three typed SNPs of PTPN22 on RA or with the role of two untyped variants.

SUBMITTER: Bourgey M

PROVIDER: S-EPMC2367482 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Modeling the effect of PTPN22 in rheumatoid arthritis.

Bourgey Mathieu M Perdry Hervé H Clerget-Darpoux Françoise F

BMC proceedings 20071218

In order to model the effect of PTPN22 on rheumatoid arthritis (RA), we determined the combination of single-nucleotide-polymorphisms (SNPs) showing the strongest association with RA. Three SNPs (rs2476601-rs12730735-rs11102685) were selected for which we estimated the genotypic relative risks (GRRs) of the corresponding genotypes. On the basis of these GRRs we defined four at-risk genotypic classes. Relative to the class of reference risk, individuals had a risk approximately multiplied by two, ...[more]

PMID: 18466535

Similar Datasets

Modeling of PTPN22 and HLA-DRB1 susceptibility to rheumatoid arthritis.

Project description:In the present paper, we used the North American Rheumatoid Arthritis Consortium data provided for Genetic Analysis Workshop 15 Problem 2 to: 1) estimate the penetrances of PTPN22 and HLA-DRB1 and, 2) test the selected model of PTPN22 conditional on the rheumatoid factor status. To achieve these aims, we used the marker association segregation chi-square method, fitting simultaneously both genotype frequency and identical by descent distributions in a sample of 3690 White individuals from 604 nuclear families. A co-dominant model fitted the rs2476601 (R620W) single-nucleotide polymorphism (SNP) of the PTPN22 gene well, whereas a lack of fit for all models was observed for the HLA-DRB1 locus. Testing genetic models of rheumatoid arthritis that include the PTPN22 SNP in addition to the HLA-DRB1 locus did not affect the results, nor did subgroup analysis of PTPN22 conditional on the rheumatoid factor status. In conclusion, PTPN22 R620W SNP is a risk factor for rheumatoid arthritis. The genetic architecture of the HLA-DRB1 locus is highly complex, and more elaborate modeling of this locus is required.

| S-EPMC2367526 | biostudies-literature

PTPN22 splice forms: a new role in rheumatoid arthritis.

Project description:Genetic variation in the protein tyrosine phosphatase non-receptor type gene 22 (PTPN22, encoding lymphoid tyrosine phosphatase, LYP) influences the risk of developing multiple autoimmune diseases, but the underlying mechanisms are not completely understood. In a recent study published in Genome Medicine, Ronninger et al. showed that there are differences in the expression of PTPN22 isoforms between peripheral blood mononuclear cells from rheumatoid arthritis patients and those of healthy controls. This study provides new insights into the role of PTPN22 in autoimmune diseases.

| S-EPMC3392759 | biostudies-literature

The PTPN22 locus and rheumatoid arthritis: no evidence for an effect on risk independent of Arg620Trp.

Project description:The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR?=?0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.

| S-EPMC2958827 | biostudies-literature

Meta-genetic association of rheumatoid arthritis and PTPN22 using PedGenie 2.1.

Project description:PedGenie beta version 2.1 is a unique, flexible, and easily implemented analysis software tool that is enhanced significantly by incorporation of meta-statistics to allow valid combined analysis of multiple studies, including mixtures of family-based and independent resources, in the detection of genetic association with common disease. Genetic Analysis Workshop 15 Problem 2 data, provided by the North American Rheumatoid Arthritis Consortium, were used to demonstrate PedGenie 2.1 meta-association testing of variants in the PTPN22 gene and rheumatoid arthritis across multiple resources containing both family-based and independent individuals. Our findings are generally consistent with previous reports for a panel of 14 single-nucleotide polymorphism (SNP) markers, including functional coding SNP R620W, in which the minor allele conferred a significant two-fold increased risk. More power to detect associations was achieved in certain analyses by using extra family-based samples, rather than restricting analyses to single cases randomly selected from each pedigree.

| S-EPMC2367587 | biostudies-literature

PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.

Project description:The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

| S-EPMC1275606 | biostudies-literature

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22.

Project description:A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22.

| S-EPMC5070957 | biostudies-literature

rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis-a possible interface?

Project description:BackgroundRheumatoid arthritis (RA) and periodontitis (PD) are proven to share common risk markers, including genetic factors. In the present study we focused on genetic variants in PTPN22 (rs2476601), PADI4 (rs2240340), CTLA4 genes (rs3087243) and its impact on RA and PD.Materials and methodsIn the study 111 RA patients and 256 systemically healthy controls were involved. A subdivision of patients and controls was carried out according the severity of periodontitis (no/level 1 PD vs. level 2 PD).ResultsI. Evaluating the genetic impact on the occurrence of RA the T allele of rs2476601 (PTPN22) (bivariate: p < 0.001; multivariate: p = 0.018) and T allele of rs2240340 (PADI4) (bivariate: p = 0.006; multivariate: p = 0.070) were associated with an increased vulnerability to RA. II. Investigating the genetic influence on level 2 PD the T allele of rs2476601 (PTPN22) was shown to be associated with a higher susceptibility to PD within the RA group (bivariate: p = 0.043; multivariate: p = 0.024). III. The T allele of rs2476601 (PTPN22) was proven to be a significant marker of RA and level 2 PD comorbidity (bivariate: p < 0.001; multivariate: p = 0.028).ConclusionsThese results support the thesis that genetic variations may represent a possible link between PD and RA. The study increases knowledge about disease-specific and cross-disease genetic pattern.

| S-EPMC7559817 | biostudies-literature

PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

Project description:PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.

| S-EPMC3299735 | biostudies-literature

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis.

Project description:Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.

| S-EPMC6556429 | biostudies-literature

Genome-wide gene-based analysis of rheumatoid arthritis-associated interaction with PTPN22 and HLA-DRB1.

Project description:The genes PTPN22 and HLA-DRB1 have been found by a number of studies to confer an increased risk for rheumatoid arthritis (RA), which indicates that both genes play an important role in RA etiology. It is believed that they not only have strong association with RA individually, but also interact with other related genes that have not been found to have predisposing RA mutations. In this paper, we conduct genome-wide searches for RA-associated gene-gene interactions that involve PTPN22 or HLA-DRB1 using the Genetic Analysis Workshop 16 Problem 1 data from the North American Rheumatoid Arthritis Consortium. MGC13017, HSPCAL3, MIA, PTPNS1L, and IGLVI-70, which showed association with RA in previous studies, have been confirmed in our analysis.

| S-EPMC2795906 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data