The Effects of Methotrexate and Genetic Polymorphisms on the Folate/Homocysteine Pathway

作者: Carolyn Summers

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摘要: High homocysteine (Hcy) and low folate status are associated with many clinical conditions ranging from cardiovascular disease to neural tube defects. Hcy levels affected by diet as well lifestyle genetic factors. Associations between polymorphisms of the enzymes involved in folate/Hcy metabolism phenotypes were examined. Genetic studied a range populations, which included healthy individuals, systemic lupus erythematosus (SLE) patients, rheumatoid arthritis (RA) families child defects (NTDs). Chronic is development “proatherosclerotic” phenotype endothelial cell line, EA.hy 926. The effect anti-folate, methotrexate (MTX), on expression inflammatory genes was 926 cells context activation TNF-α. Genotyping performed TaqMan allelic discrimination assays or size difference PCR. Total (tHcy) concentrations plasma red blood (RBC) derivatives measured stable isotope dilution liquid chromatography multiple reaction monitoring mass spectrometry. Affymetrix microarrays used assess changes gene vitro. Candidate then queried using qRT-PCR. ELISAs confirm protein levels. Several had effects tHcy not only total RBC but individual derivatives. Specifically observed within studies men, women, RA SLE patients. Also none showed an association increased risk for NTDs Transmission Disequilibrium Test analyses. pathway impact folate, may various conditions. MTX mRNA several genes, C3 IL-8. Activation TNF-α did seem be treatment MTX, exception up regulation C3. lowered intracellular altered distribution derivatives, cells. Degree Type Dissertation Name Doctor Philosophy (PhD) Graduate Group Pharmacology First Advisor Alexander S. Whitehead This dissertation available at ScholarlyCommons: http://repository.upenn.edu/edissertations/985

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