scholarly journals AB0014 METHOTREXATE - IMPLICATIONS OF PHARMACOGENETICS IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1041.2-1042
Author(s):  
R. Pinheiro Torres ◽  
F. Pimentel Dos Santos ◽  
J. Branco
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Variants ◽  
Methylenetetrahydrofolate Reductase ◽  
Chromosome 21 ◽  
Bibliographic Databases ◽  
Target Cells ◽  
Reduced Folate Carrier ◽  
Single Nucleotide ◽  
Exon 2 ◽  
Mesh Terms

Background:Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA) (1).Objectives:This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate’s kinetics and efficiency profile.Methods:A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analysed.Results:Genetic variants of four main proteins, with different functions, have been consistently described.Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most commonly studied variant of the gene is the 80G > A variant (rs1051266), mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission (2).ABC transporters are involved in the eflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T (rs1045642) is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment (3).Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors (1). The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat (rs34743033), with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity (4).The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T (rs1801133) and A1298C (rs1801131). Both are associated with a decreased efficacy and an increased toxicity of MTX (5).Conclusion:MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction, enhancing the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.References:[1]Song, G. et al. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol33, 1715–1724 (2014).[2]Hayashi H. et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet. 2013;28(2):164-8.[3]Zhu H. et al. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014 Mar;15(4):551-66.[4]Owen SA. et al. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharm J. 2013;13:227–34.[5]Hughes LB. et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2006;65:1213–8.Disclosure of Interests:None declared

scholarly journals Plasma interleukin-21 levels and genetic variants are associated with susceptibility to rheumatoid arthritis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Youguo Hao ◽  
Lijun Xie ◽  
Jing Xia ◽  
Zhen Liu ◽  
Baoxiu Yang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Variants ◽  
Chinese Population ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Das28 Score ◽  
Single Nucleotide ◽  
Chronic Inflammatory Condition ◽  
Chinese Subjects ◽  
Pro Inflammatory Cytokines

Abstract Background Rheumatoid Arthritis (RA) is a chronic inflammatory condition characterized by autoantibodies development and an elevated spectrum of pro-inflammatory cytokines. Previous reports highlighted a relationship between IL-21and the pathogenesis of RA. Although elevated IL-21 levels have been reported in RA patients, the association of common IL-21 genetic variants with a predisposition to RA development in the Chinese population lacks. Materials and methods Five hundred and fourteen Chinese subjects (healthy controls: 303 and rheumatoid arthritis patients: 211) were enrolled in the study. Clinical data of patients were collected from medical records, and patients were treated as per the guidelines. Common single nucleotide polymorphisms in the IL-21 gene (rs907715, rs2221903, rs2055979 and rs6822844) were genotyped by TaqMan SNPs genotyping method. IL-21 level in plasma of RA patients and healthy subjects was measured by ELISA. Results The plasma level of IL-21 was significantly higher in subjects with rheumatoid arthritis relative to healthy controls (p < 0.0001). A positive correlation was observed between IL-21 level and DAS28 score, indicating the association of the cytokine with the worsening of the disease (Spearman r = 0.61, p < 0.0001). The prevalence of AA genotype (rs2055979) was significantly higher in RA subjects than in the controls (p < 0.0001, χ2 = 34.73, OR = 4.34, 95% CI = 2.623 to 7.219). Furthermore, elevated plasma IL-21 was observed in the rs2055979-AA genotype compared to CC type (p < 0.0001). Conclusion IL-21 plays a crucial function in rheumatoid arthritis pathogenesis. IL-21 rs2055979 polymorphism is associated with IL-21 plasma levels and is predisposed to RA development in the Chinese population.

scholarly journals Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis

2019 ◽  
Vol 48 (2) ◽  
pp. 030006051987958 ◽  
Author(s):  
Shengli Wang ◽  
Shuguang Zuo ◽  
Zhigang Liu ◽  
Xinying Ji ◽  
Zhenqiang Yao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Effect ◽  
Fragment Length Polymorphism ◽  
Mthfr C677t ◽  
Reduced Folate Carrier ◽  
Nucleotide Polymorphisms ◽  
Independent Factor ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Poor Efficacy

Objective The objective was to explore the association of methylene tetrahydrofolate reductase ( MTHFR) C667T and A1298C and reduced folate carrier 1 ( RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China. Methods Two hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment. Results We detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity. Conclusions In Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.

scholarly journals KDR (VEGFR2) Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 355 ◽  
Author(s):  
Agnieszka Paradowska-Gorycka ◽  
Barbara Stypinska ◽  
Andrzej Pawlik ◽  
Damian Malinowski ◽  
Katarzyna Romanowska-Prochnicka ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Variants ◽  
Serum Levels ◽  
Mean Value ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Protein Levels ◽  
Codominant Model

We investigated kinase insert domain-containing receptor (KDR) polymorphisms and protein levels in relation to susceptibility to and severity of Rheumatoid Arthritis (RA). 641 RA patients and 340 controls (HC) were examined for the rs1870377 KDR variant by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method and for rs2305948 and rs2071559 KDR single nucleotide polymorphisms (SNPs) by TaqMan SNP genotyping assay. KDR serum levels were determined by enzyme-linked immunosorbent assay (ELISA). The rs1870377 KDR variant has shown association with RA under the codominant (p = 0.02, OR = 1.76, 95% CI = 1.09–2.85) and recessive models (p = 0.019, OR = 1.53, 95% CI = 1.07–2.20). KDR rs2305948 was associated with RA under the dominant model (p = 0.005, OR = 1.38, 95% CI = 1.10–1.73). Under the codominant model, the frequency of the rs2071559 TC and GG genotypes were lower in RA patients than in controls (p < 0.001, OR = 0.51, 95% CI = 0.37–0.69, and p = 0.002, OR = 0.57, 95% CI = 0.39–0.81). KDR rs2071559 T and rs2305948 A alleles were associated with RA (p = 0.001, OR = 0.60, 95% CI = 0.45–0.81 and p = 0.008, OR = 1.71, CI = 1.15–2.54). KDR rs2305948SNP was associated with Disease Activity Score (DAS)-28 score (p < 0.001), Visual Analog Scale (VAS) score (p < 0.001), number of swollen joints (p < 0.001), mean value of CRP (p < 0.001). A higher KDR serum level was found in RA patients than in HC (8018 pg/mL versus 7381 pg/mL, p = 0.002). Present results shed light on the role of KDR genetic variants in the severity of RA.

scholarly journals Tele-health interventions to support self-management in adults with rheumatoid arthritis: a systematic review

2021 ◽  
Author(s):  
Alison MacIver ◽  
Hannah Hollinger ◽  
Clare Carolan
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Of Bias ◽  
Health Interventions ◽  
Self Management ◽  
Cochrane Library ◽  
Bibliographic Databases ◽  
Published Evidence ◽  
Collection Form ◽  
Randomised Controlled

AbstractRheumatoid arthritis (RA), a long-term auto-immune condition is a challenging condition for patients to manage. Goals of treatment include reducing pain, decreasing inflammation, and improving an individual’s overall function. Increasingly technology is being utilised to support patients to self-manage their condition. The aim of this systematic narrative review was to synthesise and critically appraise published evidence concerning the effectiveness of tele-health interventions to support self-management in RA. Bibliographic databases searched from 2014 to March 2020 included MedLINE, Embase, Cochrane Library. Search strategy combined the following concepts: (1) rheumatoid arthritis, (2) tele-health interventions, and (3) self-management. Only randomised controlled trials (RCTs) involving adults with RA were included. Titles, abstracts, full-text articles were screened, any discrepancies were checked by a second reviewer. Risk of bias was assessed using Cochrane risk of bias tool and data were extracted utilising the Cochrane data collection form for RCT interventions along with the TiDier checklist. Due to high heterogeneity, results were not meta-analysed and instead data were synthesised narratively. The search identified 98 articles, seven were included. The completed RCTs varied in the nature of the interventions, duration/severity of RA, outcomes measured and effectiveness of the interventions. The completed RCTs included a total of 791 participants Disease duration was largely between 4 and 10 years and disease severity on average was moderate. There was extensive variation in intervention components, theories underpinning theories and outcomes measured. Five RCTs reported a positive effect on factors such as disease activity, medication adherence, physical activity and self-efficacy levels. This study suggests that tele-health interventions that are well-designed, tailored and multi-faceted can help to achieve positive self-management outcomes in RA. None of the studies showed evidence of harm.

scholarly journals Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabrina Samad Shoily ◽  
Tamim Ahsan ◽  
Kaniz Fatema ◽  
Abu Ashfaqur Sajib
Keyword(s):  
Diabetes Mellitus ◽  
Chronic Kidney Disease ◽  
Genetic Variants ◽  
Nucleotide Polymorphisms ◽  
Differential Distribution ◽  
East Asians ◽  
Single Nucleotide ◽  
Common Genetic Variants ◽  
Haplotype Frequencies ◽  
Variant Alleles

AbstractDiabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.

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