rs3758149

For over 70 years, methotrexate (MTX) has remained a first-line chemotherapeutic agent for acute lymphoblastic leukemia (ALL), playing a pivotal role in maintenance therapy. Understanding the genetic determinants of MTX efficacy is therefore essential for improving clinical outcomes. However, studies on MTX efficacy–related polymorphisms remain limited, particularly for non-coding variants, for which most evidence is based on statistical associations. Here, through integrative bioinformatics analysis and systematic meta-analysis, we identified rs1544105, a non-coding SNP in the folylpoly-γ-glutamate synthetase (FPGS) gene, as closely associated with MTX efficacy. Compared with the GG genotype, the AA genotype increased disease progression risk (OR: 2.23; 95% CI: 1.16–4.30; p = 0.017) and elevated plasma MTX concentration-to-dose ratios at 24 h (WMD: 2.27; 95% CI: 1.04–4.40; p = 0.002) and 40 h (WMC: 0.02; 95% CI: 0.00–0.04; p = 0.033). Using prime editing, we generated homozygous mutant (GG) 293T cells, demonstrating that rs1544105 A > G increased FPGS expression (~ 1.5-fold, p < 0.05) and intracellular MTX retention (p < 0.05). Moreover, both cell-based and animal experiments confirmed that rs1544105 A > G markedly improved MTX efficacy. Mechanistically, dual-luciferase reporter and electrophoretic mobility shift assays revealed that rs1544105 A > G enhanced the binding affinity of the SNP-containing sequence for the transcription factor CREB1, thereby increasing FPGS transcriptional activity and ultimately augmenting MTX efficacy. Our multidimensional study, integrating data analysis with cellular, molecular, and animal experiments, highlights the remarkable regulatory role of a single SNP, rs1544105, in modulating MTX therapeutic response and provides a basis for individualized MTX-based maintenance therapy in ALL patients.

2025 · Wenliang Yu, Chenyang Li, Yuning Meng, Qiang Li, Mengyue Gao, Wei Tang, Yao Li, Ziyi Tan, Xiaoran Zhou, Zeyang Liu, Yun Xu

High-dose methotrexate is commonly used to treat several types of cancer. While effective, elimination of high-dose methotrexate from the body is highly variable and delayed elimination can lead to serious and sometime life-threatening adverse events. There have been many clinical studies to better understand how genetics influence the variability in methotrexate elimination, mostly through candidate gene studies and three genome-wide association studies. Unfortunately, there are conflicting results and some studies lack the appropriate replication and validation needed to confirm their effects on methotrexate elimination. Therefore, the purpose of this systematic review was to summarize all of the germline pharmacogenetic association studies of genetic associations influencing high-dose methotrexate elimination in children with cancer. Abstract Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

2021 · Zachary L. Taylor, Jesper Vang, Elixabet Lopez–Lopez, Natanja Oosterom, Torben Stamm-Mikkelsen, Laura B. Ramsey

The current treatment strategy for rheumatoid arthritis has been formulated within the framework of the European League Against Rheumatism (EULAR) concept “Treatment to achieve the goal”. Methotrexate prescribed as soon as possible after verifying rheumatoid arthritis is recognized as a first-line drug that allows to achieve disease remission and prevent destructive changes in the joints. Long-term clinical experience of using methotrexate allowed to conclude that almost 30% patients with rheumatoid arthritis turn out to be resistant to such treatment, enforcing to change the basal anti-inflammatory therapy, shift to using targeted or genetically engineered biological drugs, so that timeframe to prevent disease progression can be irreversibly lost. In the last decade, genetic testing for drug therapy effectiveness has been gaining momentum based on individual features in functioning of enzyme systems which regulate various stages of drug biotransformation. To date, a personalized approach to treatment of rheumatoid arthritis may be implemented after examining more than a dozen of single nucleotide polymorphisms (SNPs) within the folate cycle genes responsible for metabolizing methotrexate as well as its mechanism of action. In our work, we attempted to test a relationship between therapeutic response (efficacy and resistance) to methotrexate and -401CT (rs 3758149) SNP in the GGH (gamma-glutamyl hydrolase) gene, which coordinates the processes of extracellular methotrexate transport. A groups patients consisted of 85 basic anti-inflammatory therapy-naïve patients diagnosed with rheumatoid arthritis, who were initially treated with methotrexate at a dose of 10 to 17.5 mg per week, with subsequently assessed therapeutic efficacy 6 months after the treatment onset based on dynamics in DAS28 index that allowed to identify groups of “responders” and “non-responders”. Next, all patients from select groups underwent molecular genetic typing for GGH-401CT SNP by using real-time polymerase chain reaction. Our study allowed to find that prevalence of the TT homozygous genotype (OR = 5.09; 95% CI 1.11- 23.3; p = 0.037) dominated in “methotrexate non-responders”, whereas “methotrexate responders” tended to have higher C allele frequency (OR = 0.54; 95% CI 0.27-1.01; p = 0.087), which allowed to identify them by genetic predictors of methotrexate therapeutic response in rheumatoid arthritis.

2020 · I. V. Devald, E. A. Khodus, Е. Б. Хромова, K. Yu. Myslivtsova, А. Л. Бурмистрова

近年来, 风湿病学研究迅速发展, 类风湿关节炎 (RA) 诊疗指南持续更新, 药物治疗策略不断优化. 基于《 2018 年中国类风湿关节炎诊疗指南》, 结合《 2015 年美国风湿病学会 (ACR) RA 治疗指南》,《 2016 年欧洲风湿病防治联合会 (EULAR) RA 治疗指南》 的治疗策略与用药建议, 分析各指南推荐传统合成改善病情抗风湿药 (csDMARDs) 甲氨蝶呤, 来氟米特, 柳氮磺吡啶, 羟氯喹的遗传药理学研究进展. 相关药物遗传药理学研究主要集中于药物转运体, 代谢酶, 作用靶点等方面, 研究结果可作为临床用药选择方面的参考依据, 但尚需大样本多人群的临床试验验证. (In recent years, with the rapid development of rheumatology, guidelines for the diagnosis and treatment of rheumatoid arthritis (RA) and the drug treatment strategies have been updated constantly. Based on the 2018 Chinese guideline for the diagnosis and treatment of rheumatoid arthritis and combined with the 2015 ACR guideline and the 2016 EULAR guideline, this article analyzed the research advances in the pharmacogenetics of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), including methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. The relevant studies had focused on the research of drug transporter, drug-metabolizing enzyme, and drug target. The results of the study can be used as a reference for clinical drug selection though verification from clinical trials in large populations is still needed.)

2019 · 吴明如， 葛卫红

14 (14)(rs11545078), 14269G> A (rs12681874) の遺伝子多型を同定した. 赤血球内 MTX 濃度測定は, PG 数によって MTXPG1 から MTXPG6 までの各々の濃度を高速液体クロマトグラフィー法 (liquid chromatography-tandem mass spectrometry) にて測定した. 総赤血球内 MTX 濃度は 108±12.4 nmol/L であり, 患者の内服用量依存性に細胞内濃度の増加を認めた. しかし, 同じ用量の患者群でも MTX 濃度は個々の患者で大きく変動した. そこで, PG 化の効率を評価するために, MTXPG3-5/1-2 比を求め, 前述の遺伝子多型との関連を検討した. MTXPG3-5/1-2 比は, SLC19A1 と GGH の遺伝子多型では明らかな変動を認めなかったものの FPGS の遺伝子多型に

2018 · Takeshi Yamamoto

Evaluate the potential of selected SNPs as predictors of methotrexate (MTX) therapeutic outcome...

2016 · Áurea Lima, Miguel Bernardes, Rita Azevedo, Vitor Seabra, Rui Medeiros

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal obstructive syndrome (SOS), are still largely unpredictable and remain the major causes of morbidity and mortality. Both donor and patient genetic background might influence the success of bone marrow transplantation and could at least partially explain the inter-individual variability in HSCT outcome. This review summarizes some of the recent studies on candidate gene polymorphisms in HSCT, with particular reference to pediatric cohorts. The interest is especially focused on pharmacogenetic variants affecting myeloablative and immunosuppressive drugs, although genetic traits involved in SOS susceptibility and transplant-related mortality are also reviewed.

2015 · Raffaella Franca, Gabriele Stocco, Diego Favretto, Nagua Giurici, Giuliana Decorti, Marco Rabusin

Methotrexate (MTX) is a derivative of folic acid (folate) and commonly used as an anchor drug for the treatment of rheumatoid arthritis (RA). The pharmacokinetics (PK) and pharmacodynamics (PD) of MTX entirely depends on the function of specific transporters that belong to the two major superfamilies, solute carrier transporters and ATP-binding cassette transporters. Several transporters have been identified as being able to mediate the transport of MTX, and suggested to be involved in the disposition in the body and in the regulation of intracellular metabolism in target cells, together with several enzymes involved in folate metabolism. Thus, drug-drug interactions through the transporters and their genetic polymorphisms may alter the PK and PD of MTX, resulting in an interpatient variability of efficacy. This review summarizes the PK and PD of MTX, particularly in relation to RA therapy and focuses on the roles of transporters involved in PK and PD with the aim of facilitating an understanding of the molecular basis of the mechanism of MTX action to achieve its effective use in RA therapy.

2014 · Katsuhisa Inoue, Hiroaki Yuasa