Lack of association between CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with rheumatoid arthritis.
Ontology highlight
ABSTRACT: Aim
Leflunomide is a disease-modifying antirheumatic drug used in therapy for rheumatoid arthritis (RA). Previous studies indicated that oestrogens and androgens may affect the response to leflunomide in RA patients. The synthesis of androgens is regulated by cytochrome CYB5A. The aim of this study was to examine the association between the CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with RA.Methods
The study included 111 women diagnosed with RA. Leflunomide was administered in monotherapy at a dose of 20 mg/day. All patients underwent a monthly evaluation for 12 months after the initiation of treatment with leflunomide.Results
After 12 months of therapy, the changes in individual disease activity parameters, such as: DAS28, ESR, CRP and VAS, were not statistically significantly different between rs1790834 genotypes in the Kruskal-Wallis test.Conclusions
The results of our study suggest lack of statistically significant association between the CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with RA.
SUBMITTER: Laczna M
PROVIDER: S-EPMC8528780 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IntroductionRheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene.MethodsData sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case-control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5-expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates.ResultsThe study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P=4.1*10(-3); OR=0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR=0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR=0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue.ConclusionsCYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA.
| S-EPMC4372052 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Toll-like receptor-4 (TLR4) activates the innate immune response via NF-kB pathway and mitogen-activated protein kinase signaling, leading to expression of proinflammatory cytokines and chemokines. The G allele of TLR4 rs4986790 (+896A>G, Asp299Gly) gene polymorphism has been implicated in reduction of risk of atherosclerosis. In this study, 1481 RA patients fulfilling the 1987 American College of Rheumatology (ACR) criteria were genotyped for the rs4986790 TLR4 variant to determine the influence of this variant in the risk of CV events in these patients. Also, HLA-DRB1 status was determined using molecular based methods. Moreover, potential influence of rs4986790 variant in the development of subclinical atherosclerosis was assessed in a subgroup of RA patients with no history of CV events by the measurement of surrogate markers of subclinical atherosclerosis. No statistically significant differences in allele or genotype frequencies for the rs4986790 variant between RA patients who experienced CV events or not were found. Likewise, no significant association between this gene variant and any of the surrogate markers of subclinical atherosclerosis was found. In summary, results in our study do not support the hypothesis that the rs4986790 (+896A>G, Asp299Gly) TLR4 variant may influence predisposition for subclinical atherosclerosis and clinically evident CV disease in RA patients.
| S-EPMC3391495 | biostudies-literature
Project description:Background:STAT4 rs7574865 polymorphism has been evidently associated with susceptibility to Rheumatoid Arthritis (RA) in European and Eastern Asian populations, whereas studies in other countries reported otherwise. Objective:We investigated the distribution of STAT4 rs7574865 polymorphism in a group of Syrian RA patients. Methods:Eighty-one RA patients and forty healthy controls were enrolled and STAT4 rs7574865 was genotyped by direct sequencing. RA patients were stratified according to Anti-Citrullinated Protein Antibodies (ACPA) status for analysis. Results:Minor T allele frequencies were 30.4%, 16.7%, and 23.8% in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively. No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05). Conclusion:STAT4 rs7574865 TT genotype showed a potential impact on ACPA positivity in Syrian RA patients. However, STAT4 rs7574865 effect on RA onset and severity is minor compared to other genetic factors such as HLA-DRB1 shared epitope alleles.
| S-EPMC6210524 | biostudies-literature
Project description:Controversial results concerning the association between a polymorphism rs6822844 in the interleukin (IL) 21 (IL-21) gene and rheumatoid arthritis (RA) have existed. A meta-analysis to confirm above relationships is necessary to be performed immediately. We conducted a search in the PubMed database, covering all papers published up to 20 October 2018. Overall, six case-control studies with 3244 cases and 3431 healthy controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed with both Egger's and Begg's tests. After calculation, we found that IL-21 rs6822844 polymorphism could decrease RA risk in overall genetic models (allelic contrast: OR = 0.77, 95% CI = 0.62-0.97, P=0.024; TG versus GG: OR = 0.68, 95% CI = 0.50-0.92, P=0.013, and dominant genetic model: OR = 0.72, 95% CI = 0.55-0.94, P=0.016). Similarly, stratified analysis by race, source of control, significantly decreased association was found in Asians, Caucasians and hospital-based (HB) control source. Finally, in the subgroup analysis of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status, poorly decreased relationship was detected between IL-21 rs6822844 polymorphism and RF negative and ACPA positive RA risk, respectively. No obvious evidence of publication bias was detected in overall analysis. In summary, our study indicated that IL-21 rs6822844 polymorphism was significantly associated with decreased RA susceptibility.
| S-EPMC6695501 | biostudies-literature
Project description:BackgroundEpidemiological studies have investigated the association between matrix metalloproteinase-3(MMP-3) gene-1171 5A/6A polymorphism and rheumatoid arthritis (RA), but the results were inconsistent. To evaluate the specific relationship, we performed a meta-analysis to clarify the controversies.MethodsThe relevant literatures dated to December 07th 2013 were retrieved from PubMed, EMBASE and the China National knowledge Infrastructure (CNKI) databases. The number of the alleles and genotypes for MMP-3 were obtained. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association between MMP-3 5A/6A promoter polymorphism and RA. All of the statistical analyses were conducted by STATA11.0 software.ResultsA total of 6 case-control studies covering 1451 cases and 1239 controls were included in the final meta-analysis. There was no significant association between MMP-3 5A/6A promoter polymorphism and RA in all genetic models (for 6A versus 5A: OR=1.19, 95% CI=0.91-1.56, P=0.203; 5A/6A versus 5A/5A: OR=1.31, 95% CI=0.89-1.92, P=0.174; 6A/6A versus 5A/5A: OR=1.78, 95% CI=0.68-4.61, P=0.238; the recessive model: OR=1.48, 95% CI=0.88-2.47, P=0.141; and the dominant model: OR=1.46, 95% CI=0.71-3.00, P=0.299). In the subgroup analysis by ethnicity, we obtained the similar results.ConclusionsWe systematically investigate the association between MMP-3-1171 5A/6A polymorphism and RA susceptibility; however, the results show a lack of correlation. Considering the small sample size and the selection bias existed in some studies, further studies are needed to confirm the findings.
| S-EPMC4247749 | biostudies-literature
Project description:IntroductionMultifunctional pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated in a variety of inflammatory diseases including rheumatoid arthritis (RA). TNF-α polymorphisms are mostly located in its promoter region and play a significant role in disease susceptibility and severity. We therefore sought to investigate TNFA -863C/A (rs1800630) polymorphism association with RA activity in our Pakistani study group.Material and methodsA total of 268 human subjects were enrolled. Among them, 134 were RA patients and 134 were controls. In this study the physical parameters of RA patients were collected, and the disease activity was measured by DAS28. The genotypes were determined following the allele-specific PCR along with the pre-requisite internal amplification controls. Subsequently, data were analyzed statistically for any significant association including χ2/Fisher's exact test using GraphPad prism 6 software.ResultsWe found that the TNF-α -863 C/A (rs1800630) variant was not differentially segregated between cases and controls in either genotype frequency, with χ2 of 2.771 and a p-value of 0.2502, or allele frequency, with χ2 of 2.741 and a p-value of 0.0978, with an odds ratio (95% CI) of 0.7490 (0.5317-1.055).ConclusionsThe lack of positive association of TNF-α -863(rs1800630) polymorphism in our study group implies that TNF-α -863 polymorphism is not a susceptible marker to RA and cannot serve as a genetic factor for screening RA patients in Pakistan. There might be other factors that may influence disease susceptibility. However, further investigations on additional larger and multi-regional population samples are required to determine the consequences of genetic variations for disease prognosis.
| S-EPMC6425217 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is the most common systemic inflammatory disease and is of unknown etiology. The altered balance between immunosuppressive and inflammatory T cell subpopulations exerts a huge impact on RA pathogenesis. The STAT3 protein regulates genes involved in the immune responses. It regulates maturation of T and B cells. Its abnormal activity is significantly associated with autoimmune diseases and cancer development. We aimed to evaluate the contribution of three potentially functional single nucleotide polymorphisms (SNPs) within the STAT3 gene to susceptibility and severity of RA in the Polish population.A total of 595 patients with RA and 330 healthy individuals were included in the study. DNA from patients and healthy subjects was obtained from peripheral blood using standard DNA isolating methods. The STAT3 rs1053005, rs1026916 and rs2293152 polymorphisms were genotyped using the TaqMan SNP genotyping assay. The accuracy of SNP genotyping was confirmed using direct DNA sequence analysis.The distribution of STAT3 polymorphisms did not differ significantly between cases and controls. Our results revealed a tendency only, where rs1026916 AA genotype occurred more frequently in RA patients compared to healthy controls, in codominant (p = 0.09), dominant (p = 0.06) and recessive (p = 0.09) models. STAT3 rs2293152 polymorphism was associated with higher DAS28 (p = 0.014 codominant model; p = 0.003 dominant model), increased number of swollen joints (p = 0.02), higher VAS (p = 0.01) and higher HAQ score (p = 0.05).We did not observe a significant association between the three studied STAT3 genetic variants and increased susceptibility to or severity of RA. Only the STAT3 rs2293152 polymorphism was associated with parameters that indicate a more severe course of the disease. However, its distribution did not differ between RA and control groups. According to our observations these 3 studied STAT3 SNPs may not be used as risk factors for developing RA.
| S-EPMC5974628 | biostudies-literature
Project description:No consistent results have been reached on the relationship of interleukin-1 (IL-1) rs1800587 polymorphism with the susceptibility to rheumatoid arthritis (RA) so far. Therefore, the current meta-analysis was designed to thoroughly review relevant studies, in order to examine the relationship of IL-1A rs1800587 polymorphism with RA risk. Electronic databases were retrieved for literature regarding the relationship between IL-1A rs1800587 polymorphism and RA vulnerability according to the inclusion and exclusion criteria. Stata 12.0 software was adopted to examine the enrolled literature. Meanwhile, odds ratio (OR) and corresponding 95% confidence intervals (95% CI) were used to evaluate the association. A total of seven case-control researches (3267 patients and 2960 healthy controls) were eventually enrolled into the current meta-analysis. Our data indicated no correlation of IL-1A rs1800587 polymorphism with RA risk (TT vs CC: OR = 0.90, 95% CI = 0.73-1.11; TC vs CC: OR = 1.02, 95% CI = 0.78-1.34; Dominant model: OR = 1.04, 95% CI = 0.80-1.35; Recessive model: OR = 1.91, 95% CI = 0.74-1.12). Similarly, no association was found in subgroup analysis stratified by ethnicity. Our findings indicated no relationship between IL-1A rs1800587 polymorphism and RA vulnerability.
| S-EPMC10455026 | biostudies-literature
Project description: Not available
| S-EPMC9637842 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the development of CV disease in patients with RA. 2136 Spanish RA patients were genotyped for the rs3212780 and rs3212752 JAK3 gene polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 539 of these patients by carotid ultrasonography (US). No statistically significant differences were found when each polymorphism was assessed according to carotid intima-media thickness values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV events after adjusting for potential confounders. In conclusion, our results do not confirm association between JAK3 polymorphisms and CV disease in RA.
| S-EPMC4359874 | biostudies-literature