Pharmacogenetic insights into MTHFR and SLC19A1 variants in low-dose methotrexate therapy for rheumatologic diseases

The identification of genetic markers that will enable accurate diagnosis and prediction of the therapy outcome is a crucial step in managing rheumatologic and autoimmune diseases. Low-dose methotrexate is a mainstay therapeutic agent for treatment. The objective of this review is to summarize the data on candidate single nucleotide polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and solute carrier family 19 member 1 (SLC19A1) genes involved in methotrexate pathways. Over the past decade, several functional polymorphisms affecting methylenetetrahydrofolate reductase activity have been studied in the context of low-dose methotrexate therapy. The most frequently investigated polymorphisms are rs1801133 (c.665C>T) and rs1801131 (c.1286A>C) in MTHFR gene and rs1051266 (c.80A>G) in SLC19A1 gene. Although the effects of these polymorphisms are remaining unclear, several studies have shown association with adverse effect while fewer studies have demonstrated association with remission or positive response to methotrexate. However, there is scarcity research in Latin American population assessing the influence of genetic variants in the pharmacokinetics and pharmacodynamics of methotrexate in the context of interethnic admixture. There is an urgent need of to expand these studies and to support the development of clinical pharmacogenomics guidelines.