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EBioMedicine
. 2026 Jan 6:123:106111.
doi: 10.1016/j.ebiom.2025.106111. Online ahead of print. Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity
Claudio Cappadona 1 , Valeria Rimoldi 1 , Francesca Tettamanzi 1 , Giulia Cardamone 1 , Alberto Mantovani 2 , Giulia Soldà 3 , Elvezia Maria Paraboschi 1 , Rosanna Asselta 1
Affiliations
Background: 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.
Methods: 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).
Findings: 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", "oxidative phosphorylation", and "inflammatory response" pathways. Transcriptomics showed a proinflammatory profile in hospitalised patients (N = 24) and a prothrombotic signature in ICU-admitted individuals (N = 35), reflecting disease progression. Genomic and transcriptomic data integration 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 (1873 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 neutralise ROS, contributing to COVID-19 progression.
Interpretation: In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a candidate susceptibility gene.
Funding: Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.
Keywords: COVID-19; Immune response; Lactoperoxidase; Multi-omics; Oxidative stress; Thrombosis.
. 2026 Jan 6:123:106111.
doi: 10.1016/j.ebiom.2025.106111. Online ahead of print. Multi-omics identifies oxidative stress, prothrombotic pathways, and lactoperoxidase variants as key factors in COVID-19 severity
Claudio Cappadona 1 , Valeria Rimoldi 1 , Francesca Tettamanzi 1 , Giulia Cardamone 1 , Alberto Mantovani 2 , Giulia Soldà 3 , Elvezia Maria Paraboschi 1 , Rosanna Asselta 1
Affiliations
- PMID: 41500120
- DOI: 10.1016/j.ebiom.2025.106111
Background: 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.
Methods: 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).
Findings: 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", "oxidative phosphorylation", and "inflammatory response" pathways. Transcriptomics showed a proinflammatory profile in hospitalised patients (N = 24) and a prothrombotic signature in ICU-admitted individuals (N = 35), reflecting disease progression. Genomic and transcriptomic data integration 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 (1873 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 neutralise ROS, contributing to COVID-19 progression.
Interpretation: In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a candidate susceptibility gene.
Funding: Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.
Keywords: COVID-19; Immune response; Lactoperoxidase; Multi-omics; Oxidative stress; Thrombosis.