biostudies-literatureUnknown123Cappadona CGoverno Italiano Ministero dell&amp;apos;Istruzione dell&amp;apos;Università e della Ricerca<h4>Background</h4>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in ∼200,000 COVID-19-related deaths. Unravelling host genetic factors underlying disease severity is key to understanding progression mechanisms.<h4>Methods</h4>We applied multi-omics approaches to investigate genetic susceptibility to COVID-19 severity in the Italian population. We combined an exome-wide case-control study of rare germline variants (215 severe/critically ill patients vs 1755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalised patients to identify signatures associated with severe respiratory outcomes (ICU admission).<h4>Findings</h4>Rare variant analysis revealed significant aEBioMedicine106111https://www.ebi.ac.uk/biostudies/studies/S-EPMC12809084biostudies-literatureMulti-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity.PMC12809084Paraboschi EMAsselta RCappadona CRimoldi VCardamone GTettamanzi FMantovani ASolda GfalseMulti-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity.<h4>Background</h4>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in ∼200,000 COVID-19-related deaths. Unravelling host genetic factors underlying disease severity is key to understanding progression mechanisms.<h4>Methods</h4>We applied multi-omics approaches to investigate genetic susceptibility to COVID-19 severity in the Italian population. We combined an exome-wide case-control study of rare germline variants (215 severe/critically ill patients vs 1755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalised patients to identify signatures associated with severe respiratory outcomes (ICU admission).<h4>Findings</h4>Rare variant analysis revealed significant a2026-01-01T00:00:00Z2026 Jan2026-07-15T07:45:30.871Z2026-07-01T03:08:01.369ZS-EPMC128090844150012010.1016/j.ebiom.2025.106111