<i>ABCB1</i>and<i>ABCC3</i>Gene Polymorphisms Are Associated with First-year Response to Methotrexate in Juvenile Idiopathic Arthritis

Rotte, Maurits C F J de; Bulatović, Maja; Heijstek, Marloes W; Jansen, Gerrit; Heil, Sandra G.; Schaik, Ron H.N. van; Wulffraat, Nico; Jonge, Robert de

doi:10.3899/jrheum.111593

Cited by 62 publications

(50 citation statements)

References 49 publications

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“…With the use of a personalized-medicine approach, genetic variations (SNPs) and metabolites (folate, MTX-polyglutamates) within the MTX pathway (one-carbon fingerprint) were analyzed to predict the outcome of MTX treatment in RA. Beyond clinical parameters (body mass index, smoking) and baseline disease severity, genetic factors that were associated with unresponsiveness to MTX included SNPs in the efflux transporters ABCB1 (rs1045642 G > A) and ABCC3 (rs4793665 T > C), and methionine synthesis (MTRR, rs1801394 A > G) [90,91]. Furthermore, low baseline erythrocyte folate and erythrocyte MTX-polyglutamate levels after 3 months of treatment were predictive for a decreased MTX response [92].…”

Section: Antifolates In Immune Diseasesmentioning

confidence: 98%

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

Jansen

Peters

2015

Pteridines

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AbstractFolate receptors and transporters as well as folate enzymes play an essential role in human disease and form important targets for the treatment of immune diseases and cancer. To discuss new developments in this area, every 2 years a multidisciplinary meeting is held, which aims to be an informal forum for fundamental scientists and clinicians. During this meeting, the regulation of folate transporters and folate enzymes is discussed at the level of expression, transcription, translation, post-translational modification, and splicing and enzyme regulation. Importantly, this knowledge is applied and translated into exciting clinical applications by clinicians with various backgrounds, such as surgeons, nephrologists, rheumatologists and oncologists. Moreover, the meeting provides an excellent forum for a scientific interaction between academia and industry.

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Section: Antifolates In Immune Diseasesmentioning

confidence: 98%

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

Jansen

Peters

2015

Pteridines

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“…A more recent pharmacogenomic study showed that a SNP of ¹211C>T ABCC3 (rs4793665), which is located in the promoter region of ABCC3 gene and reported to reduce the expression of its mRNA, is associated with weaker response to MTX in patients with juvenile idiopathic arthritis, 79) suggesting that lower expression of ABCC3 could alter the PK/PD of MTX. It is also possible to assume a potential role of ABCC3 in the regulation of intracellular levels of MTX in the target cells.…”

Section: Transporters Involved In the Pharmacokinetics Of Mtxmentioning

confidence: 99%

“…On the other hand, numerous studies on pharmacogenomics have demonstrated the association between ABCB1 polymorphism and the effectiveness of MTX in RA therapy. 3435C>T (rs1045642), a synonymous SNP of ABCB1 that occurs with higher frequency, has been shown to be associated with the response, probability of symptom remission and incidence of adverse events in the therapy with MTX in patients with RA 78) or juvenile idiopathic arthritis, which is one of the most common chronic rheumatic diseases in childhood, 79) although conflicting observations have also been reported. 80) Since 3435C>T is a silent mutation without apparent functional change of ABCB1 protein, the mechanism of the modulation of the effect of MTX in vivo remains unclear.…”

Section: Transporters Involved In the Pharmacokinetics Of Mtxmentioning

confidence: 99%

Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

Inoue

Yuasa

2014

Drug Metabolism and Pharmacokinetics

121

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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.

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“…We thank Dr. Ranganathan for her interesting comments 1 on our work 2 . In our recently published prediction model for methotrexate (MTX) nonresponse in juvenile idiopathic arthritis (JIA) 3 , ABCB1 rs1045642 was described, indicating the relative importance of this polymorphism to predict nonresponse to MTX in JIA.…”

Section: To the Editormentioning

confidence: 99%

Dr. de Rotte, et al reply

Rotte

Bulatović²,

Heijstek³

et al. 2013

J Rheumatol

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ABCB1andABCC3Gene Polymorphisms Are Associated with First-year Response to Methotrexate in Juvenile Idiopathic Arthritis

Cited by 62 publications

References 49 publications

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

Dr. de Rotte, et al reply

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