(147) MTHFR Allele and One-Carbon Metabolic Profile Predict Severity of COVID-19 Disease

Introduction/Rationale: Alterations in the methionine cycle, a key component of the one-carbon metabolism pathway that is critical for viral propagation and disease progression, may serve as early indicators of severe SARS-CoV-2 infection.

Methods: As part of the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we performed a longitudinal analysis of untargeted plasma metabolic profiles of hospitalized adult COVID-19 patients followed from admission to 1-year post-discharge. Using a 7-point ordinal scale, patients were clustered into 5 disease trajectory groups based on respiratory illness during hospitalization and targeted metabolomics was assessed using liquid chromatography-mass spectrometry.

Results: Metabolic profiling revealed that patients in more severe disease trajectory groups (TG4-TG5) showed alterations in the methionine cycle. Specifically, S-adenosylmethionine (SAM), a methyl group donor important for gene expression and methylation of DNA, RNA and proteins, was highly abundant among the more severe trajectory groups (TG4-TG5) compared to the less severe trajectory groups (TG1-TG3). In addition, we identified the C766T allele mutation of the MTHFR gene, a common polymorphism, as a genetic contributor to the methionine pathway and predictor of disease trajectory.

Conclusion: These results highlight the potential of metabolic characterization of the methionine pathway in combination with screening for the common genetic MTHFR variant as a practical approach for precision COVID-19 management.