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RHEUMATOLOGY / CLINICAL RESEARCH
Association of genetic polymorphisms on methotrexate toxicity in patients with rheumatoid arthritis
1
Department of Pharmacy and Pharmaceutical Technology, Social and Legal Assistance Pharmacy Section, Faculty of Pharmacy, University of Granada, Granada, Spain
2
Clinical Analysis Service, Hospital Campus de la Salud, Granada, Spain
3
Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen Macarena, Sevilla, Spain
4
Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Granada, Spain
5
Department of Biochemistry, Faculty of Pharmacy, University of Granada, Granada, Spain
Submission date: 2020-02-05
Final revision date: 2020-05-27
Acceptance date: 2020-06-09
Online publication date: 2020-07-17
Publication date: 2026-03-24
Corresponding author
Cristina Pérez Ramírez
University Hospital Virgen Macarena Pharmacy Service Dr. Fedriani 3 41009 Sevilla, Spain Phone: +34955008000
University Hospital Virgen Macarena Pharmacy Service Dr. Fedriani 3 41009 Sevilla, Spain Phone: +34955008000
Arch Med Sci 2026;22(1):179-187
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Methotrexate (MTX) is the treatment of choice for patients with rheumatoid arthritis (RA). However, it has been found to produce toxicity in some patients. Different polymorphisms can play a part in inter-individual differences in toxicity. Our aim is therefore to determine the influence of gene polymorphisms in the MTX metabolic pathway, such as MTHFR (rs1801133 and rs1801131), MTHFD1 (rs2236225), MTR (rs1805087), and ABCC2 (rs4148396), on toxicity in MTX treatment among Caucasian patients diagnosed with RA.
Material and methods:
Real-time polymnerase chain reaction (PCR) analysis with TaqMan probes was performed on these polymorphisms in 200 patients in a retrospective study.
Results:
Patients with TT genotype and C allele for MTHFR rs1801133 gene polymorphism presented a higher risk of anaemia (p = 0.0304; OR = 3.70; 95% CI: 1.10–12.34) and dizziness (p = 0.0438; OR = 8.15; 95% CI: 1.61– 148.68). Patients with MTHFR rs1801131-C allele or CC genotype presented a higher risk of mucositis (p = 0.0188; OR = 3.02; 95% CI: 1.22–7.91), acneiform rash (p = 0.0322; OR = 5.74; 95% CI: 1.34–39.21), and alopecia (p = 0.0072; OR = 5.11; 95% CI: 1.37–17.70). Patients with MTR rs1805087- CC genotype presented a higher risk of anosmia (p = 0.0038; OR = 98.00; 95% CI: 3.16–infinite); patients with the TT genotype or T allele for MTHFD1 rs2236225 presented a higher risk of liver failure (p = 0.00229; OR = 2.34; 95% CI: 1.14–4.96) and alopecia (p = 0.0248; OR = 3.83; 95% CI: 1.10–13.30), and patients with the TT genotype for ABCC2 rs4148396 polymorphism (p = 0.0466; OR = 2.67; 95% CI: 0.98–6.94) presented a higher risk of headaches.
Conclusions:
Pharmacogenomic analysis of these polymorphisms may facilitate decision-making in relation to MTX treatment toxicity among RA patients.
Methotrexate (MTX) is the treatment of choice for patients with rheumatoid arthritis (RA). However, it has been found to produce toxicity in some patients. Different polymorphisms can play a part in inter-individual differences in toxicity. Our aim is therefore to determine the influence of gene polymorphisms in the MTX metabolic pathway, such as MTHFR (rs1801133 and rs1801131), MTHFD1 (rs2236225), MTR (rs1805087), and ABCC2 (rs4148396), on toxicity in MTX treatment among Caucasian patients diagnosed with RA.
Material and methods:
Real-time polymnerase chain reaction (PCR) analysis with TaqMan probes was performed on these polymorphisms in 200 patients in a retrospective study.
Results:
Patients with TT genotype and C allele for MTHFR rs1801133 gene polymorphism presented a higher risk of anaemia (p = 0.0304; OR = 3.70; 95% CI: 1.10–12.34) and dizziness (p = 0.0438; OR = 8.15; 95% CI: 1.61– 148.68). Patients with MTHFR rs1801131-C allele or CC genotype presented a higher risk of mucositis (p = 0.0188; OR = 3.02; 95% CI: 1.22–7.91), acneiform rash (p = 0.0322; OR = 5.74; 95% CI: 1.34–39.21), and alopecia (p = 0.0072; OR = 5.11; 95% CI: 1.37–17.70). Patients with MTR rs1805087- CC genotype presented a higher risk of anosmia (p = 0.0038; OR = 98.00; 95% CI: 3.16–infinite); patients with the TT genotype or T allele for MTHFD1 rs2236225 presented a higher risk of liver failure (p = 0.00229; OR = 2.34; 95% CI: 1.14–4.96) and alopecia (p = 0.0248; OR = 3.83; 95% CI: 1.10–13.30), and patients with the TT genotype for ABCC2 rs4148396 polymorphism (p = 0.0466; OR = 2.67; 95% CI: 0.98–6.94) presented a higher risk of headaches.
Conclusions:
Pharmacogenomic analysis of these polymorphisms may facilitate decision-making in relation to MTX treatment toxicity among RA patients.
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