The Effects of Methotrexate and Genetic Polymorphisms on the Folate/Homocysteine Pathway
Abstract
High homocysteine (Hcy) and low folate status are associated with many clinical conditions ranging from cardiovascular disease to neural tube defects. Hcy and folate levels are affected by diet as well as lifestyle and genetic factors. Associations between genetic polymorphisms of the enzymes involved in folate/Hcy metabolism and Hcy levels and folate phenotypes were examined. Genetic polymorphisms were studied in a range of populations, which included healthy individuals, systemic lupus erythematosus (SLE) patients, rheumatoid arthritis (RA) patients, and families with a child affected by neural tube defects (NTDs). Chronic low folate is associated with development of a “proatherosclerotic” phenotype in the endothelial cell line, EA.hy 926. The effect of the anti-folate, methotrexate (MTX), on the expression of inflammatory genes was studied in EA.hy 926 cells in the context of folate status and activation by TNF-α.\nGenotyping was performed by TaqMan allelic discrimination assays or by size difference PCR. Total Hcy (tHcy) concentrations and levels of plasma and red blood cell (RBC) folate derivatives were measured by stable isotope dilution liquid chromatography multiple reaction monitoring mass spectrometry. Affymetrix microarrays were used to assess changes in gene expression in vitro. Candidate inflammatory genes were then queried using qRT-PCR. ELISAs were performed to confirm changes in protein levels.\nSeveral polymorphisms had effects on tHcy levels and not only on…
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