Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis

Qiu, Qi; Huang, Jing; Shu, Xi; Fan, Huizheng; Zhou, Youwen; Xiao, Cheng

doi:10.1038/srep44015

Cited by 51 publications

(51 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 .…”

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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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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…Except for association of recessive and codominant models of rs1801131 in a South Asian population, there has been no evidence for either of these 2 SNPs being related to the efficacy of MTX in RA according to various meta‐analyses . A recent meta‐analysis has showed associations between the MTX response in RA patients for MTHFR A1298C, but not for MTHFR C677T (rs1801133) .…”

Section: Current Knowledge About Pharmacogenetics Of Adsmentioning

confidence: 99%

“…ATIC C347G (rs2372536) is another well‐studied variant related to MTX therapy in RA. Despite the lack of association between rs2372536 polymorphism and the MTX treatment response in some studies, other studies, including meta‐analyses, support the association between rs2372536 polymorphism and MTX response status in some populations . Moreover, another SNP in this gene (ATIC T675C [rs4673993]) may possibly predict responsiveness to MTX in RA patients …”

Section: Current Knowledge About Pharmacogenetics Of Adsmentioning

confidence: 99%

“…In addition to SNPs on the MTHFR and ATIC genes, several other SNPs also have been reported to be associated with MTX responsiveness. For example, the association between the IL1B and IL1RN polymorphisms, KIR2DS2 and KIR2DL2, CHST11, SLC19A1 A > G (rs2838956) and AMPD1 34C > T and the response to MTX in RA patients has been detected. TYMS, an important enzyme in the de novo pyrimidine pathway responsible for DNA replication is also probably involved in treatment with MTX.…”

Section: Current Knowledge About Pharmacogenetics Of Adsmentioning

confidence: 99%

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Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

2018

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For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.

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The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New‐Onset Rheumatoid Arthritis

Artacho

Isaac

Nayak

et al. 2021

Arthritis & Rheumatology

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Objective. Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA.Methods. We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug-naive patients with new-onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome-driven MTX depletion and clinical response.Results. Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes.Conclusion. Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new-onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.

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Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis

Cited by 51 publications

References 44 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

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New‐Onset Rheumatoid Arthritis

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