Sepsis is a dysregulated host response to infection and a leading cause of global mortality, yet effective targeted therapies remain lacking. Here, we applied a proteogenomic framework integrating large-scale human genetics with circulating proteomics to identify therapeutic targets. In a meta-analysis of genome-wide association studies of 60,314 sepsis cases and 1,464,733 controls, we identified four genome-wide significant loci, including a missense variant in SERPINA1, encoding alpha-1 antitrypsin (AAT), that was also associated with 30-day sepsis mortality in the UK Biobank.

Mendelian randomization (MR) and colocalization analyses supported a causal and protective effect of higher genetically predicted circulating AAT levels on sepsis risk. The protective association was highly specific to acute infectious phenotypes, including pneumonia, and was not observed for non-infectious traits. In two independent cohorts (UK Genomic Advances in Sepsis and the Biobanque Québécois sur la COVID-19), circulating AAT increased markedly during acute illness but was significantly attenuated among missense variant carriers in a dose-dependent manner, consistent with impaired protease-antiprotease balance.

MR of the AAT-regulated proteome recapitulated findings from prior sepsis trials, both negative and positive, providing orthogonal genetic support for therapeutic modulation of this pathway. Together, these findings provide the first human genetic evidence for AAT’s causal role in sepsis, positioning SERPINA1 as a high-priority candidate for drug repurposing and targeted therapeutic interventions.

J.B.R. acknowledges investigator-initiated grant funding to his institution from Roche, Eli Lilly, GlaxoSmithKline, and Biogen for projects unrelated to the submitted work. J.B.R. is the Chief Executive Officer of and holds equity in 5Prime Sciences (www.5primesciences.com), a company providing genetics-based drug development research services. K.Y.H.L. is an employee of 5Prime Sciences, and T.L. provides consulting services to the company. 5Prime Sciences was not involved in the design, execution, analysis, interpretation, or funding of this study, and these commercial relationships are unrelated to the current research. All other authors declare no competing interests.

D.T. is supported by the Fonds de recherche du Québec-Santé (FRQS). T.M.Z. is supported by the Canada First Research Excellence Fund and the Fonds de recherche du Québec through the D2R Initiative at McGill University. C.Y.S. is supported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship Doctoral Award (reference number: 187673), an FRQS doctoral training scholarship, and a Lady Davis Institute/TD Bank Scholarship. T.L. is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award number R35GM162188, as well as start-up funding from the Office of the Vice Chancellor for Research and Graduate Education, the School of Medicine and Public Health, and the Department of Population Health Sciences at the University of Wisconsin-Madison. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. G.B.L. receive salary support from the FRQS.

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MVP, FinnGen, Genes & Health, and TPMI GWASs are publicly available on their respective websites. Accessing AoU and UKB data for GWAS requires an application through the respective official processes. We will upload the meta-analysis GWAS conducted in this study to GWAS Catalog upon publication. Proteomics data of UK GAinS are available on the Proteomics Identification Database (PRIDE) (accession ID PXD039875). GAinS genotyping data were deposited at the European Genome-phenome Archive (EGA), under accession number EGAD0000101536969. Proteomics and genomics data of BQC19 are available upon request (https://www.bqc19.ca/en/home/).

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MVP, FinnGen, Genes & Health, and TPMI GWASs are publicly available on their respective websites. Accessing AoU and UKB data for GWAS requires an application through the respective official processes. We will upload the meta-analysis GWAS conducted in this study to GWAS Catalog upon publication.

Proteomics data of UK GAinS are available on the Proteomics Identification Database (PRIDE) (accession ID PXD039875). GAinS genotyping data were deposited at the European Genome-phenome Archive (EGA), under accession number EGAD0000101536969. Proteomics and genomics data of BQC19 are available upon request (https://www.bqc19.ca/en/home/).