234: MTHFR genotype and methionine metabolism predict COVID-19 severity

Petrova B et al., Proc Natl Acad Sci U S A - IMPACC longitudinal metabolomics and genomics analyses show that disruptions in one‑carbon/methionine metabolism together with MTHFR C677T genotype at hospital admission improve prediction of severe COVID‑19 and long COVID risk. Key terms: mthfr, one-carbon metabolism, methionine, metabolomics, long covid.

Study Highlights:
IMPACC profiled plasma metabolites (global and targeted) from over 1,000 hospitalized COVID-19 patients and identified early alterations in one‑carbon metabolism, with emphasis on the methionine cycle. Methionine‑sulfoxide and S‑adenosylhomocysteine (SAH) were elevated in patients with more severe clinical trajectories and changed over serial visits. The common hypomorphic MTHFR C677T (AA) genotype associated with distinct methionine‑cycle metabolite profiles and, when combined with baseline methionine, methionine‑sulfoxide, and SAH levels, significantly improved mortality prediction versus genotype alone. The combined genotype–metabolite factor also stratified risk of long COVID across patient‑reported outcome clusters.

Conclusion:
Integrating MTHFR C677T status with early plasma methionine‑cycle metabolite measurements can enhance early risk stratification for severe COVID‑19 and long COVID.

Music:
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Article title:
MTHFR allele and one-carbon metabolic profile predict severity of COVID-19

First author:
Petrova B

Journal:
Proc Natl Acad Sci U S A

DOI:
10.1073/pnas.2509118122

Reference:
Petrova B, Syphur C, Montgomery RR, Levy O, Diray‑Arce J, Kleinstein SH, Kanarek N, Culhane AJ, Chen J, et al. MTHFR allele and one‑carbon metabolic profile predict severity of COVID‑19. Proc Natl Acad Sci U S A. 2025;122(51):e2509118122. https://doi.org/10.1073/pnas.2509118122

License:
CC BY 4.0 International License (CC BY 4.0)

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-20.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in the transcript: one-carbon metabolism and methionine cycle; MTHFR C677T polymorphism; IMPACC cohort design with visit-1 sampling within 72 hours; early metabolite perturbations (methionine, methionine sulfoxide, SAH, glycine, serine); two-hit hypothesis; predictive modeling (AI
- transcript topics: One-carbon metabolism and the methionine cycle; MTHFR C677T polymorphism and AA homozygosity; IMPACC cohort design and visit-1 sampling within 72 hours; Early metabolite changes: methionine, methionine sulfoxide, SAH, glycine, serine; Long COVID risk and trajectory analyses; Two-hit hypothesis and predictive modeling (AIC)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Combined MTHFR AA genotype with acute methionine-cycle metabolite levels (SAH, methionine, methionine sulfoxide) improves prediction of mortality and long COVID risk
- Visit 1 samples were collected within 72 hours of hospital admission
- SAH and methionine sulfoxide levels are elevated with highe...