5PSQ-056 Pharmacogenetic influence of<i>MTHFR</i>variants on methotrexate toxicity: unveiling predictive biomarkers for personalised therapy

<h3>Background and Importance</h3> Pharmacogenetics plays a crucial role in optimising drug therapy. Methylenetetrahydrofolate reductase (<i>MTHFR</i>) gene, encodes an enzyme involved in folate metabolism, which is essential for nucleotide synthesis and DNA methylation. Methotrexate, a widely used chemotherapeutic and immunosuppressant, exerts inhibits dihydrofolate reductase, thereby variations in the <i>MTHFR</i> gene influence methotrexate metabolism, potentially affecting therapeutic outcomes and the risk of suffering adverse effects (AE). Identifying the patient’s <i>MTHFR</i> genotype can provide insights for individualised dosing strategies and minimising toxicity. Different <i>MTHFR</i> metaboliser phenotypes are categorised based on genotypes, typically classified as normal(GG), intermediate (GA), or poor metabolisers (AA), depending on the presence of polymorphisms such as C677T. However, current guidelines lack robust evidence to support mtx dose adjustments based on <i>MTHFR</i> genotypes, underscoring the need for further research to validate pharmacogenetic-guided dosing strategies. <h3>Aim and Objectives</h3> The objective of this study is to evaluate the impact of <i>MTHFR</i> gene variants on the susceptibility to methotrexate-related AE. <h3>Material and Methods</h3> Observational, retrospective, and single-centre study including all patients for whom pharmacogenetic analysis of <i>MTHFR</i> was requested between February 2021 and July 2024.Socio-demographic, clinical, and therapeutic variables were collected using electronic prescription system(HCIS) and Servolab analysis software. The <i>rs1801133</i> variant of the <i>MTHFR</i> gene was genotyped using OpenArray technology. <h3>Results</h3> A total of 145 patients were genotyped, of whom 75 finally initiated methotrexate therapy. The average age of these patients was 29 years, with 44% being male. Of these, 29 patients were treated for rheumatic/dermatological diseases and 46 for paediatric leukaemias. 16 of the 75 patients analysed (21.36%) had the high-risk toxicity variant (AA). Out of them eight suffered any adverse effect: two cytopenias, one digestive intolerance, two mucositis, one bone pain, one hypertrasaminaemia, one hepatocellular hepatitis and one skin rash. 29 patients (38,67%) had the intermediate risk toxicity variant (GA), eight of them suffered from any AE: three skin rash, three digestive intolerance, one hypertransaminea and two lymphopenia. 30 patients (40%) had the low-risk toxicity variant (GG), five of them suffered from an adverse effect: two mucositis oral thrush and one skin rash. <h3>Conclusion and Relevance</h3> Our real-world data are consistent with some studies that relate MTHFR C677T mutations with an increased risk of methotrexate toxicity, particularly myelosuppression and hepatotoxicity in paediatric patients receiving high-dose MTX. However, due to the small sample size and inconsistent reports in the literature, additional studies are needed to clarify the role of MTHFR polymorphisms in MTX toxicity and efficacy. <h3>References and/or Acknowledgements</h3> <h3>Conflict of Interest</h3> No conflict of interest