Preprint VEGFA Sex-Specific Signature is associated to long COVID Symptom Persistence, 2025, Ramon et al

Abstract:
Background. Long COVID involves persistent symptoms after COVID-19 recovery, affecting multiple organ systems for months or years. Risk factors include female sex, prior chronic conditions, severe SARS-CoV-2 infection, reinfections, and lack of vaccination. As a major public health concern, ongoing research continues to investigate its causes, mechanisms, and long-term effects.

Methods. Proteomic expression analysis of 171 individuals, in two time points, with confirmed SARS-CoV-2 infection, including 133 long COVID patients from the deeply characterized COVICAT cohort, assessed 1,395 protein biomarkers using Olink® technology. Statistical analyses with linear mixed models examined protein expression changes, long COVID status, and sex-specific differences. Functional analysis included Gene Set Enrichment Analysis (GSEA) and protein–protein interaction (PPI) networks.

Findings. Findings revealed dysregulated chemokine signaling, complement activation, and viral reactivation, aligning with prior studies, and identified VEGFA overexpression in long COVID patients (effect size 0.322, SE = 0.098, p = 0.0013), along with sex-specific expression patterns. Network analysis detected 109 nodes and 274 edges, with VEGFA ranking highest across all centrality metrics.

Interpretation. By integrating comprehensive proteomic data from a well-characterized cohort, we identified sexually dimorphic patterns in protein expression in long COVID patients. Sex-based differences in protein dynamics suggest distinct immune and vascular recovery trajectories. VEGFA's role in ovarian function, cyclical expression, and uterine involvement may explain sex differences in long COVID susceptibility.

Link | PDF (SSRN preprint, May 2025, open access)