A Novel MTHFR Isoform-based Biomarker for RA and SLE

This is the authors' abstract. We don't add key points for this paper.

Objective: Disease-and drug-related biomarkers are the basis of personalized medicine by guiding patient-specific clinical decisions.The methylene-tetrahydrofolate reductase (MTHFR) gene-associated C677T polymorphism has garnered particular attention because it can lead to an amino acid change resulting in a catalytically compromised enzyme.Here, we provide an alternative interpretation of C677T-associated MTHFR phenotypes that does not exclude the original hypothesis but rather places it in a different context.Our duon-based theory has practical implications as it facilitates the development of a new predictive biomarker for Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Methods:The new MTHFR promoter was identified using the 5'RACE method and functionally characterized in transient expression studies.Western blotting and confocal microscopy were used to investigate the subcellular localization of MTHFR isoforms.Expression of MTHFR transcript variants was monitored by qRT-PCR and a gene expression index (Li/Si score) was calculated from the C t values.Results: A new MTHFR isoform was identified, driven by a novel promoter region that overlaps with the site of the C677T polymorphism.Quantitative monitoring of the catalytically active and the catalytically inactive isoforms' expression revealed that the proportion of MTHFR isoforms could be altered in PBMCs in a disease-specific manner.The calculated Li/Si scores were found to be characteristic for specific subgroups of RA and SLE patients. Conclusion:Differential expression of MTHFR isoforms provides a foundation on which a predictive biomarker (Li/Si score) could be developed for RA and SLE reflecting disease susceptibility and drug response.