MTHFR allele and one-carbon metabolic profile predict severity of COVID-19

• 成果类型: Article
• 署名作者: Petrova, Boryana; Syphurs, Caitlin; Culhane, Andrew J.; Chen, Jing; Chen, Ernie; Cotsapas, Chris; Esserman, Denise; Montgomery, Ruth R.; Kleinstein, Steven H.; Smolen, Kinga K.; Mendez, Kevin; Lasky-Su, Jessica; Steen, Hanno; Levy, Ofer; Diray-Arce, Joann; Kanarek, Naama
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Medical University of Vienna; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Yale University; Yale University; Yale University; Yale University; Yale University; Yale University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2509118122
• 发表日期: 2025-12-23
• 页码: 2509118122
• 关键词: long COVID; severe COVID risk factors; genetic predisposition; plasma metabolic signature; MTHFR; POST-ACUTE SEQUELAE; METHYLENETETRAHYDROFOLATE REDUCTASE; model selection

摘要

While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are thousands of new hospitalizations and hundreds of deaths per week in the United States, many of whom develop long COVID. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here, we report an untargeted, longitudinal plasma metabolomics study of COVID-19 patients. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. Targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a preexisting contributor to disease trajectory-patients that show aberrant one-carbon metabolite levels and that are homozygous for the MTHFR C677T, have higher incidence of severe COVID. Our results raise the possibility that MTHFR variant status may inform precision COVID-19 treatment strategies.