title: Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.
abstract: Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidalSalmonellabacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected withSalmonellahad prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Liuyang
authors.identifier: 0000-0001-9556-2361
authors.initials: L
authors.lastname: Wang
authors.affiliation: Duke Regional Hospital, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.; Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, School of Medicine, Duke University, Durham, NC 27708, USA.
authors.forename: Emily R
authors.identifier: 0000-0002-9438-1566
authors.initials: ER
authors.lastname: Ko
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, U.K.; Department of Paediatrics, University of Oxford, Oxford OX3 9DU, U.K.
authors.forename: James J
authors.initials: JJ
authors.lastname: Gilchrist
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Kelly J
authors.identifier: 0000-0003-1580-7889
authors.initials: KJ
authors.lastname: Pittman
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, U.K.
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, U.K.
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.affiliation: Proteomics and Metabolomics Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Proteomics and Metabolomics Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
authors.forename: Raymond J
authors.identifier: 0000-0001-8849-9325
authors.initials: RJ
authors.lastname: Langley
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Sarah L
authors.identifier: 0000-0002-9554-3117
authors.initials: SL
authors.lastname: Jaslow
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Raul E
authors.initials: RE
authors.lastname: Salinas
authors.affiliation: Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: D Clayburn
authors.identifier: 0000-0001-5945-3504
authors.initials: DC
authors.lastname: Rouse
authors.affiliation: Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, School of Medicine, Duke University, Durham, NC 27708, USA.; Proteomics and Metabolomics Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: M Arthur
authors.identifier: 0000-0001-9907-738X
authors.initials: MA
authors.lastname: Moseley
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Clinical Research Programme, Kilifi 80108, Kenya.
authors.forename: Salim
authors.initials: S
authors.lastname: Mwarumba
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Clinical Research Programme, Kilifi 80108, Kenya.
authors.forename: Patricia
authors.initials: P
authors.lastname: Njuguna
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Clinical Research Programme, Kilifi 80108, Kenya.
authors.forename: Neema
authors.initials: N
authors.lastname: Mturi
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Clinical Research Programme, Kilifi 80108, Kenya.; Department of Medicine, Imperial College, Norfolk Place, London W2 1PG, U.K.
authors.forename: Thomas N
authors.identifier: 0000-0003-4456-2382
authors.initials: TN
authors.lastname: Williams
authors.affiliation: Kenya Medical Research Institute-Wellcome Trust Clinical Research Programme, Kilifi 80108, Kenya.; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.
authors.forename: J Anthony G
authors.identifier: 0000-0001-7533-5006
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, U.K.; Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, School of Medicine, Duke University, Durham, NC 27708, USA.; Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.; Medical Service, Durham Veterans Affairs Health Care System, Durham, NC 27705, USA.
authors.forename: Christopher W
authors.identifier: 0000-0001-7240-2453
authors.initials: CW
authors.lastname: Woods
authors.affiliation: Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, School of Medicine, Duke University, Durham, NC 27708, USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
authors.affiliation: Duke Center for Applied Genomics & Precision Medicine, Department of Medicine, School of Medicine, Duke University, Durham, NC 27708, USA.; Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.; Emergency Medicine Service, Durham Veterans Affairs Health Care System, Durham, NC 27705, USA.
authors.forename: Ephraim L
authors.identifier: 0000-0002-6417-2042
authors.initials: EL
authors.lastname: Tsalik
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.; Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Ko
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000097:blood / Q000235:genetics; D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study; D000074705:Human Genetics; D006801:Humans; D000069550:Machine Learning; D008297:Male; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D012475:Salmonella; D012480:Salmonella Infections / Q000097:blood / Q000235:genetics / Q000401:mortality; D018805:Sepsis / Q000097:blood / Q000235:genetics / Q000401:mortality
chemical_list: D015415:Biomarkers; D000241:Adenosine
keywords: APIP; SIRS; Salmonella; biomarker; cytokine; inflammation; methionine salvage; methylthioadenosine; pyroptosis; sepsis