An Allele of the MTHFR one-carbon metabolism gene predicts severity of COVID-19
Boryana Petrova, Caitlin Syphurs, Andrew J Culhane, Jing Chen, Ernie Chen, Chris Cotsapas, Denise Esserman, Ruth Montgomery, Steven Kleinstein, Kinga Smolen, Kevin Mendez, Jessica Lasky-Su, Hanno Steen, Ofer Levy, Joann Diray-Arce, Naama Kanarek
doi:10.1101/2025.02.28.25323089
While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, the emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are > 10,000 new hospitalizations per week in the U.S., many of whom develop post-acute sequelae of SARS-CoV-2 (PASC), or "long COVID", with long-term health issues and compromised quality of life. 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 and longitudinal metabolomic study of plasma derived from adult patients with COVID-19. Onecarbon 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. A follow-up 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. The methionine cycle produces Sadenosylmethionine (SAM), the methyl group donor important for methylation of DNA, RNA, and proteins, and its high abundance was reported to correlate 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 pre-existing predictor of disease trajectory -patients homozygous for the MTHFR C677T have higher incidence of experiencing NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. severe disease. Our results raise the possibility that screening for the common genetic MTHFR variant may be an actionable approach to stratify risk of COVID severity and may inform novel precision COVID-19 treatment strategies.
Yale School of Public Health, New Haven, CT 06510, USA: Denise Esserman, Leying Guan, Anderson Brito, Jessica Rothman, Nathan D. Grubaugh
IMPACC Network Competing Interests The Icahn School of Medicine at Mount Sinai has filed patent applications related to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and therapeutics, listing Florian Krammer and Viviana Simon as co-inventors. Mount Sinai has spun out Kantaro to market SARS-CoV-2 serological tests and Castlevax to develop SARS-CoV-2 vaccines, with Florian Krammer as co-founder and scientific advisory board member of Castlevax. Florian Krammer has consulted for Merck, Curevac, Seqirus, GSK, Pfizer, 3rd Rock Ventures, Sanofi, Gritstone, and Avimex. His laboratory collaborates with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics development. Ofer Levy is a named inventor on patents held by Boston Children's Hospital related to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK) and Pfizer and he is a co-founder and advisor to Ovax, Inc., which develops opioid vaccines. Charles Cairns consults for bioMérieux and receives grant funding from the Bill & Melinda Gates Foundation. James A. Overton is a consultant at Knocean Inc.
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