Association of functional variants of PTPN22 and tp53 in psoriatic arthritis: a case-control study.
Ontology highlight
ABSTRACT:
SUBMITTER: Butt C
PROVIDER: S-EPMC1526561 | biostudies-literature | 2006
REPOSITORIES: biostudies-literature
Publications
Association of functional variants of PTPN22 and tp53 in psoriatic arthritis: a case-control study.
Butt Christopher C Peddle Lynette L Greenwood Celia C Hamilton Sean S Gladman Dafna D Rahman Proton P
Arthritis research & therapy 20060103 1
Recent studies have implicated PTPN22 and tp53 in susceptibility to several autoimmune diseases, including rheumatoid arthritis, suggesting that these genes are important in maintaining immune homeostasis. Because autoimmune diseases may share similar susceptibility loci, investigation of these genes in psoriatic arthritis (PsA) is of potential relevance. As a result we investigated known coding polymorphisms in PTPN22 and tp53 in a homogenous Caucasian PsA cohort from Newfoundland, Canada and a ...[more]
Similar Datasets
Project description:INTRODUCTION: The purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls. METHODS: A total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls. RESULTS: Carriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (?2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005). CONCLUSIONS: In this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.
| S-EPMC3132030 | biostudies-literature
Project description:ObjectiveThe PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data.MethodsA total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies.ResultsThe PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis.ConclusionsThe PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.
| S-EPMC3174938 | biostudies-literature
Project description:PurposeVariants in the gene encoding Programmed Cell Death-1 (PDCD1) have been associated with susceptibility to Systemic Lupus Erythematosus and other autoimmune diseases. Given that clinically distinct autoimmune phenotypes share common genetic susceptibility factors, variants in PDCD-1 were tested for a possible association with Juvenile Idiopathic Arthritis (JIA).MethodsFour Single Nucleotide Polymorphisms (SNPS) in the PDCD1 gene were genotyped and analyzed: rs7421861, rs11568821, rs10204525, and rs7568402 in 834 cases and 855 controls of Northern European ancestry. Each variant was examined for possible associations with JIA and then analyzed for association with JIA categories.ResultsPDCD1 variants showed no association with JIA in the cohort overall (rs7421861 p=0.63, rs11568821 p=0.13, rs10204525 p=0.31, and rs7568402 p=0.45). Stratification by JIA categories indicated a significant association between systemic JIA and PDCD1 rs7568402 (OR=0.53, p=0.0027), which remained significant after 10,000 permutations, but was not replicated in an independent multi-ethnic systemic JIA cohort. A nominal association between enthesitis-related arthritis and rs115668821 was also observed (OR=0.22, p=0.012).ConclusionUnlike other multiple autoimmune disease associated genetic variants, there was no association between PDCD1 variants and JIA or JIA categories.
| S-EPMC5759045 | biostudies-literature
Project description:BackgroundPsoriatic arthritis (PsA) is associated with increased cardiovascular morbidity and mortality. The aims of our real-life study were to compare the prevalence of cardiovascular risk factors (CVRFs) and cardiovascular events (CVEs) among patients with PsA with a control population, to evaluate the impact of correcting factors in equations that assess cardiovascular risk (CVR) in PsA, and to determine the percentage of patients who reach the LDLc target as indicated by the European guidelines.MethodsIn this observational cross-sectional monocentric case-control study, we used a standardized procedure to systematically assess patients with PsA aged 25-85 years who met the Classification for Psoriatic Arthritis (CASPAR) criteria. Controls were extracted from the MOnitoring NAtionaL du rISque Artériel (MONALISA) study. We compared the prevalence of CVRFs, CVEs, the CVR, and the percentage of patients reaching recommended LDLc target in both populations. The CVR was first assessed using SCORE and QRISK2 equations. Then, the SCORE equation was corrected by applying a 1.5 multiplication factor, as recommended by EULAR for rheumatoid arthritis (SCORE-PsA), and the QRISK2 was corrected using the "rheumatoid arthritis" item (QRISK2-PsA).ResultsA total of 207 PsA and 414 controls were included. CVRFs and CVEs were more frequent in the PsA group. After controlling for age and gender, atherothrombotic disease was increased in the PsA population (SCORE p = 0.002, QRISK2 p = 0.001). Using the SCORE-PsA increased the percentage of patients with a high or very high CVR from 39.3 to 45.3% in the PsA group. Similarly, using the QRISK2-PsA increased the percentage of patients with a CVR ≥ 10% from 44.9 to 53.2%. The percentages of patients with PsA with high LDLc in the high and very high CVR groups were not significantly different from controls, despite a trend in favor of patients with PsA. Of the 83 PsA with a QRISK2 ≥ 10%, only 22.9% were treated with statin vs. 35.8% of the 134 controls. The QRISK2-PsA score did not alter these results.ConclusionIn real-life, patients with PsA have a higher prevalence of CVRFs, as well as a higher prevalence of CVEs compared to the general population. The CVR is higher in the PsA population than in the controls either using the SCORE and QRISK2 equations or using the corrected SCORE- PsA and QRISK2-PsA equations.
| S-EPMC9160333 | biostudies-literature
Project description:IntroductionThe TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk.MethodsAllelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals.ResultsNo significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34).ConclusionThe lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing.
| S-EPMC1175066 | biostudies-literature
Project description:The purpose of this study was to identify functional genetic variants in the promoter of tumor necrosis factor superfamily member 15 (TNFSF15) and evaluate their effects on the risk of developing gastric adenocarcinoma. Forty DNA samples from healthy volunteers were sequenced to identify single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter. Two TNFSF15 SNPs (-358 T > C and -638 A > G) were identified by direct sequencing. Next, genotypes and haplotypes of 470 gastric adenocarcinoma patients and 470 cancer-free controls were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Serologic tests for Helicobacter pylori infection were measured by enzyme-linked immuno-sorbent assay (ELISA). Subjects carrying the TNFSF15 -358 CC genotype were at an elevated risk for developing gastric adenocarcinoma, compared with those with the -358 TT genotype (OR 1.42, 95% CI, 1.10 to 2.03). H. pylori infection was a risk factor for developing gastric adenocarcinoma (OR 2.31, 95% CI, 1.76 to 3.04). In the H. pylori infected group, subjects with TNFSF15 -358 CC genotype were at higher risks for gastric adenocarcinoma compared with those carrying -358 TT genotype (OR: 2.01, 95%CI: 1.65 to 4.25), indicating that H. pylori infection further influenced gastric adenocarcinoma susceptibility. The -358 T>C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the -358 C containing haplotypes showed significantly decreased luciferase expression compared with -358 T containing haplotypes. Collectively these findings indicate that functional genetic variants in TNFSF15 may play a role in increasing susceptibility to gastric adenocarcinoma.
| S-EPMC4176965 | biostudies-literature
Project description:ObjectiveMethotrexate (MTX) is a commonly used disease-modifying antirheumatic drug in psoriatic arthritis, but there is conflicting evidence to support its efficacy.MethodsWithin the Tight Control of Psoriatic Arthritis (TICOPA) study, patients were treated with MTX as part of the tight control protocol or standard care. Outcomes were recorded at the 12-week visit, including joint counts, skin, nail, enthesitis, dactylitis, and patient-reported measures.ResultsOf the 206 patients enrolled, 188 received MTX in the first 12 weeks of the trial with 104 receiving a mean dose > 15 mg/week. The proportions of patients achieving the American College of Rheumatology (ACR) outcomes at 12 weeks were ACR20 40.8%, ACR50 18.8%, and ACR70 8.6%, with 22.4% achieving minimal disease activity. Improvements were seen in psoriasis with 27.2% reaching a Psoriasis Area and Severity Index (PASI) 75. The proportion of patients with dactylitis and Leeds dactylitis instrument (LDI) scores decreased significantly (62.7% decrease in patients with dactylitis, median change LDI -59.7, -157.4 to -26.4, p = 0.033). The decrease in proportion of patients with enthesitis (25.7%) was significant, but the median change in enthesitis score was 0. There was a trend to higher proportions of patients receiving over 15 mg/week achieving ACR20, ACR50, and PASI75.ConclusionDespite the open-label design of the data, improvements in multiple clinical outcomes were seen. The proportion of patients reaching ACR20 in the TICOPA study was higher than in the Methotrexate in Psoriatic Arthritis study (41% vs 34%), but no comparative data are available for other outcomes. There is a suggestion of a dose response, but this is hard to assess when patients doing well may be maintained on lower doses.
| S-EPMC4740927 | biostudies-literature
Project description:IntroductionIn recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling.MethodsTo identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay.ResultsNone of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility.ConclusionsThus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population.
| S-EPMC3446458 | biostudies-literature
Project description:BACKGROUND: The tumour supressor gene TP53 is thought to be involved in neural apoptosis. The polymorphism at codon 72 in TP53 and the long form variants of the upstream variable number of tandem repeats (uVNTR) polymorphism in the dopamine D4 receptor (DRD4) gene are reported to confer susceptibility to schizophrenia. METHODS: We recruited 934 patients with schizophrenia and 433 healthy individuals, and genotyped the locus of the TP53 codon 72 and DRD4 uVNTR polymorphisms by combining the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) with direct sequencing. RESULTS: No significant differences were found in the frequency of the genotype of the TP53 codon72 polymorphism between patients with schizophrenia and their controls. However, the long form alleles (> or = 5 repeats) of the DRD4 uVNTR polymorphism were more frequent in patients with schizophrenia than in controls (p = 0.001). Hence, this class of alleles might be a risk factor for enhanced vulnerability to schizophrenia (odds ratio = 3.189, 95% confidence interval = 1.535-6.622). In the logistic regression analysis, the long form variants of the DRD4 polymorphism did predict schizophrenia after the contributions of the age and gender of the subjects were included (p = 0.036, OR = 2.319), but the CC and GG genotypes of the codon 72 polymorphism of TP53 did not. CONCLUSIONS: The long form variants of the uVNTR polymorphism in DRD4 were associated with schizophrenia, in a manner that was independent of the TP53 codon 72 polymorphism. In addition, given that the genetic effect of the TP53 codon 72 polymorphism on the risk of developing schizophrenia was very small, this polymorphism is unlikely to be associated with schizophrenia. The roles that other single nucleotide polymorphisms (SNPs) in the TP53 gene or in other apoptosis-related genes play in the synaptic dysfunction involved in the pathogenesis of schizophrenia should be investigated.
| S-EPMC2808306 | biostudies-literature
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