Influence of FPGS rs1544105 and GGH rs3758149 Gene Polymorphisms on Methotrexate Pharmacogenetics.

Abstract

Methotrexate (MTX) pharmacogenetics has been extensively investigated due to the high inter-individual variability in response to treatment. This wide variability can lead to treatment discontinuation or even death. Several genes involved in the pharmacodynamics and pharmacokinetics of MTX have been studied. However, there are still no guidelines for pharmacogenetics-guided MTX dosing. The FPGS rs1544105 and GGH rs3758149 gene polymorphisms were genotyped and their allele frequencies were determined. Their associations with MTX treatment response and toxicity in Uruguayan adults with haematological malignancies receiving high-dose MTX were analyzed. A worldwide systematic review of the association of these gene polymorphisms with response and toxicity to high-dose MTX treatment was also conducted. The allele frequencies of FPGS rs1544105 were 0.54 and 0.46 (C and T, respectively), and of GGH rs3758149 were 0.77 and 0.23 (C and T, respectively). Several associations were found between toxicity (gastrointestinal, hepatic and hematological) and the FPGS rs1544105 T allele (p = 0.01, p < 0.001 and p = 0.04, respectively) and between mucositis and the FPGS TT genotype (p < 0.001). The GGH rs375814 TT genotype was associated with gastrointestinal and hepatic toxicity (p = 0.01 and p < 0.001, respectively). Both the FPGS rs1544105 C allele and the GGH rs3758149 TT genotype were associated with remission (p < 0.001 and p = 0.04, respectively). The systematic review identified 247 publications and finally included 17 research articles. Few consistent data were found due to the lack of homogeneity between study groups.