Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

Qiu, Qi; Huang, Jing; Yang, Lin; Shu, Xi; Fan, Huizheng; Tu, Zhihua; Zhou, Youwen; Xiao, Cheng

doi:10.1097/md.0000000000006337

Cited by 35 publications

(36 citation statements)

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“…In our previously published studies, a total of 4 SNPs were identified in 2 genes that encode membrane‐spanning proteins involved in MTX metabolism. These gene polymorphisms were amplified by polymerase chain reaction (PCR), for which the forward and reverse primers were designed by Primer 5 software, as shown in Table .…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we searched all of the available studies that have explored relationships between single‐nucleotide polymorphisms (SNPs) or variable number of tandem repeat polymorphisms and MTX outcomes in RA patients. Thirty studies were included in our meta‐analysis, and we found that polymorphisms in 2 membrane‐spanning protein‐encoding genes, reduced folate carrier‐1 (RFC‐1)/SLC19A1 (G>A [rs7499], A>G [rs2838956], and 180G>A [rs1051266]) and ABCB1 (rs1045642), are associated with responsiveness to MTX in RA patients . RFC is the first recognized folate transporter whose function as a bidirectional anion exchanger creates an uphill influx of folates, coupled with the downhill efflux of organic phosphates, such as thiamine monophosphate and pyrophosphate .…”

mentioning

confidence: 99%

“…Thirty studies were included in our meta-analysis, and we found that polymorphisms in 2 membrane-spanning protein-encoding genes, reduced folate carrier-1 (RFC-1)/SLC19A1 (G>A [rs7499], A>G [rs2838956], and 180G>A [rs1051266]) and ABCB1 (rs1045642), are associated with responsiveness to MTX in RA patients. 11,12 RFC is the first recognized folate transporter whose function as a bidirectional anion exchanger creates an uphill influx of folates, coupled with the downhill efflux of organic phosphates, such as thiamine monophosphate and pyrophosphate. 13 ABCB1 transports various hydrophobic drugs and some anionic drugs or drug conjugates, including antifolates and MTX.…”

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confidence: 99%

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Membrane‐Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population

Liu

Fan

Yang

et al. 2019

The Journal of Clinical Pharma

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Methotrexate (MTX) is a first‐line disease‐modifying antirheumatic drug for rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. The differences in drug efficacy and adverse drug reactions may be caused by genetic variations. We investigated the effects of single‐nucleotide polymorphisms (SNPs) in 2 genes encoding membrane‐spanning proteins, namely, reduced folate carrier‐1 RFC‐1/SLC19A1 (G>A [rs7499], A>G [rs2838956] and 180G>A [rs1051266]) and adenosine triphosphate–binding cassette B1 (rs1045642). Tagged SNPs were genotyped in 162 patients with RA in China. Then, we analyzed the relationships between these SNPs and therapeutic outcomes related to MTX in Chinese RA patients. No significant associations were found between the RFC‐1/SLC19A1 (G>A [rs7499] and A>G [rs2838956]) and adenosine triphosphate–binding cassette B1 (rs1045642) gene polymorphisms and the response to MTX in RA patients. However, MTX‐related toxicity was associated with one SNP, RFC‐1 rs1051266 AA vs GG (odds ratio, 6.523; 95% confidence interval, 1.596–26.565; P = .009). SLC19A1 A>G rs2838956 showed a trend toward a significant association (odds ratio, 0.377; 95% confidence interval, 0.124–1.143; P = .085) with toxicity. Our results suggest that the RFC‐1 80G>A (rs1051266) SNP exerts a potentially protective effect against the risk of adverse drug reactions in Chinese RA patients treated with MTX. Further studies are required to validate these findings.

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Membrane‐Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population

Liu

Fan

Yang

et al. 2019

The Journal of Clinical Pharma

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“…Multiple meta-analyses have used pharmacogenetic studies to summarize how the efficacy, toxicity, and other adverse reactions of conventional DMARDs, such as methotrexate [2,7,8], and biologics [3] such as adalimumab and etanercept can be influenced by genetics. These studies point to polymorphisms in a variety of genes associated with a particular medication's metabolism, transport, target, and/or mechanism of action as a reason to why response to medication varies among patients.…”

Section: Introductionmentioning

confidence: 99%

Berberine delays onset of collagen induced arthritis through T cell suppression

Vita¹,

Lyons²,

Aljobaily³

et al. 2019

Preprint

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RUNNING TITLE (less than 50 characters): Berberine delays onset of collagen arthritis model KEY WORDS (5 words not in the title): CIA, berberine, RA, autoimmune, T cell ABSTRACT (250 words or less): Previous evidence suggests that berberine (BBR), a clinically relevant plant-derived alkaloid, alleviates symptoms of clinically apparent collagen induced arthritis (CIA), and may have a prophylactic role from in vitro studies. Thus, we used a CIA model to determine if BBR merits further exploration as a prophylactic treatment for rheumatoid arthritis. Mice were treated with either 1 mg/kg/day of BBR or a vehicle (PBS) control via IP injections from day 0 to day 28, were left untreated (CIA control), or were in a non-arthritic control group. Incidence of arthritis in BBR mice was 40%, compared to 90% in the CIA and 80% in the PBS controls. Populations of B cells and T cells from the spleens and draining lymph nodes were examined from mice across treatment groups on day 14 and from the remaining mice on day 28 when arthritic signs and symptoms were expected to be apparent. BBR-treated mice had significantly reduced populations of CD4 + T cells, CXCR5 + T fh cells, and an increased proportion of T reg at both day 14 and day 28 endpoints, as well as decreased CD28 + and CD154 + CD4 + T cells at day 14. BBR-treated mice also experienced a significant reduction of CD19 + B cells in LNs at day 28. Additionally, BBR treatment resulted in significantly lower anti-collagen type II-specific (anti-CII) IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement, and that its effect may be mediated through T cell suppression, which indirectly affects B cell activity. and PBS controls ( Fig. 2B). When comparing anti-CII IgG levels between arthritic and nonarthritic mice within the BBR group specifically, however, anti-CI IgG1, IgG2a and total IgG were all significantly reduced in the non-arthritic mice compared to those who developed arthritis (Fig. 2C). Additionally, there appeared to be a vehicle-specific effect on circulating anti-CII IgG in which the administration of PBS with 0.01% DMSO elicited elevated levels of anti-CII IgG1 and total IgG in vehicle control mice ( Fig. 2A-B).Key CD4 + T cell population characteristics in response to berberine treatment-On day 14, we observed a significant reduction in populations of both CD4 + T cells and CXCR5 + T fh cells in the LNs and spleen of BBR-treated mice (Fig. 3A-B), as well as a reduction in the percentage of CD28 + and CD154 + CD4 + T cells in the spleen and LNs of BBR-treated mice (Fig. 3A-B). By the day 28 experimental endpoint we continued to observe a significant reduction in CD4 + T cells and CXCR5 + T fh cells in the spleen and LNs of BBR-treated mice ( Fig. 3C-D), however, there was no significant difference in the percentage of CD28 + and CD154 + CD4 + T cells between treatment groups (Fig 3C-D). Berberine treatment leads to increased proportion of FOXP3 + CD25 + CD4 + T cells-To examineBBRs effect on ...

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“…journals.viamedica.pl/ginekologia_polska 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in homocysteine and methionine metabolism [3]. Since MTHFR involves in folate metabolism and MTX acts as a folate antagonist, efficacy of MTX in patients with MTHFR gene polymorphisms has been an area of interest [4,5]. In this regard, certain polymorphisms in this gene have been shown to alter MTHFR enzyme's catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

Common Methylenetetrahydrofolate Reductase Polymorphisms (A1298C & C677T) in Ectopic Trophoblasts and Methotrexate Treatment Failure in Tubal Pregnancies

et al. 2018

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Objectives: The success rate of methotrexate (MTX) therapy varies among tubal ectopic pregnancies. Common methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T&A1298C) have been suggested to alter MTX effect. This study aimed to assess and compare MTX treatment failure rates with respect to MTHFR polymorphisms in trophoblasts of ectopic tubal pregnancies. Material and methods: A retrospective chart review of tubal ectopic pregnancies was conducted and 34 eligible cases were found. Paraffinized blocks of ectopic trophoblastic tissues were retrieved from the archives of pathology department. Common MTHFR polymorphisms were studied on microdissected trophoblastic tissues. Sixteen cases with history of failed MTX therapy (study group) and 18 control cases were compared for their pertinent clinical characteristics and common MTHFR polymorphisms (C677T&A1298) data. Results: In the study group, there were 8 (50%) C677T single nucleotide polymorphisms (SNP) and 9 (56.7%) A1298C SNP. Polymorphism rates were not found to be different between two groups for neither polymorphism (p > 0.05 for both). Number of compound heterozygotes was 3 (18.7%) in study group and 5 (27.7%) in controls (p = 0.693). In addition, MTHFR polymorphism presence seemed to have no effect on interval serum β-hCG concentration change in MTX-fail group (p=0.693). Conclusions: Our data implied that common MTHFR polymorphisms of ectopic trophoblastic tissue are not associated with MTX failure in patients with tubal pregnancies. Additionally, serum β-hCG concentration changes caused by MTX treatment and studied MTHFR polymorphisms are likely independent.

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Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

Cited by 35 publications

References 57 publications

Membrane‐Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population

Membrane‐Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population

Berberine delays onset of collagen induced arthritis through T cell suppression

Common Methylenetetrahydrofolate Reductase Polymorphisms (A1298C & C677T) in Ectopic Trophoblasts and Methotrexate Treatment Failure in Tubal Pregnancies

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