Dataset related to article "Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity"

This record contains raw data related to article "Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity" Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in approximately 200,000 COVID-19-related deaths. Unraveling host genetic factors underlying disease severity is key to understanding progression mechanisms. Here, we applied integrative bioinformatics and 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 critically ill patients vs 1,755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalized patients to identify signatures associated with severe respiratory outcomes (ICU admission, 35/59). Rare variant analysis revealed significant associations with genes implicated in oxidative stress and mitochondrial dysfunction, including MTERF1 (FDR=7.69×10⁻⁵), TDP1 (FDR=3.23×10⁻⁷), and LPO(FDR=1.58×10⁻²). Pathway analyses confirmed enrichment in “reactive oxygen species” (ROS), “oxidative phosphorylation”, and “inflammatory response” pathways. Transcriptomic data showed a pro-inflammatory profile in hospitalized patients and a pro-thrombotic signature in ICU-admitted individuals, reflecting disease progression. Integration of genomic and transcriptomic data highlighted LPO, encoding the antimicrobial enzyme lactoperoxidase, as the only gene both significantly enriched for damaging variants and upregulated in ICU-admitted cases (log₂FC=0.57, FDR=0.028). Notably we confirmed the genetic association with severity in independent cohorts (1,873 cases vs 508,532 controls; meta-analysis p=0.0050, OR=3.44, 95% CI=1.71–6.89). We propose that LPO haploinsufficiency may impair host capacity to neutralize ROS, contributing to COVID-19 progression. In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a novel candidate gene in disease susceptibility.