{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:50:48Z","timestamp":1782395448879,"version":"3.54.5"},"posted":{"date-parts":[[2026,3,27]]},"group-title":"Intensive Care and Critical Care Medicine","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>SERPINA1<\/jats:italic>\n                  , encoding alpha-1 antitrypsin (AAT), that was also associated with 30-day sepsis mortality in the UK Biobank.\n                <\/jats:p>\n                <jats:p>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 Qu\u00e9b\u00e9cois 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.<\/jats:p>\n                <jats:p>\n                  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\u2019s causal role in sepsis, positioning\n                  <jats:italic>SERPINA1<\/jats:italic>\n                  as a high-priority candidate for drug repurposing and targeted therapeutic interventions.\n                <\/jats:p>","DOI":"10.64898\/2026.03.25.26349312","type":"posted-content","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:10:18Z","timestamp":1774635018000},"source":"Crossref","is-referenced-by-count":0,"title":["Human Genetic Analysis Reveals Circulating Alpha-1 Antitrypsin Level as a Protective Factor in Sepsis"],"prefix":"10.64898","author":[{"given":"Dandan","family":"Tan","sequence":"first","affiliation":[{"name":"Lady Davis Institute, Jewish General Hospital, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Quantitative Life Sciences Program, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7063-7769","authenticated-orcid":false,"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9674-5991","authenticated-orcid":false,"given":"Thomas M.","family":"Zheng","sequence":"additional","affiliation":[{"name":"Lady Davis Institute, Jewish General Hospital, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Quantitative Life Sciences Program, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin Y.H.","family":"Liang","sequence":"additional","affiliation":[{"name":"Lady Davis Institute, Jewish General Hospital, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"5 Prime Sciences Inc, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6071-4660","authenticated-orcid":false,"given":"Chen-Yang","family":"Su","sequence":"additional","affiliation":[{"name":"Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Multiomic Science, Queen Mary University of London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-5698","authenticated-orcid":false,"given":"Tianyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Brent","family":"Richards","sequence":"additional","affiliation":[{"name":"Lady Davis Institute, Jewish General Hospital, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"5 Prime Sciences Inc, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Twin Research, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Y.","family":"Chong","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick R.","family":"Lawler","sequence":"additional","affiliation":[{"name":"Division of Cardiology, McGill University Health Centre, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergus","family":"Hamilton","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Infection Sciences, North Bristol NHS Trust, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-2209","authenticated-orcid":false,"given":"Alexander J.","family":"Mentzer","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, University of Oxford, Oxford, UK"},{"name":"Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian C.","family":"Knight","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5388-0396","authenticated-orcid":false,"given":"Guillaume","family":"Butler-Laporte","sequence":"additional","affiliation":[{"name":"Lady Davis Institute, Jewish General Hospital, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Quantitative Life Sciences Program, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, UK"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Division of Infectious Diseases, McGill University Health Centre, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062506150839000_2026.03.25.26349312v3.1","doi-asserted-by":"crossref","unstructured":"Hancock, R. 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