Integrated Multi-Omics Analyses Identify TYMP as a Candidate Protective Immunoregulatory Marker in CD4⁺ T Cells...

Cellular heterogeneity in sepsis complicates the identification of cell-specific therapeutic targets. We aimed to identify genetically supported candidate immunogenetic regulators associated with sepsis through integrative multi-omics analyses.

We conducted an integrative observational multi-omics study combining single-cell expression quantitative trait locus-based Mendelian randomization (sc-eQTL MR), bulk transcriptomic survival analysis, genetic colocalization, single-cell RNA sequencing (scRNA-seq), and a prospective observational clinical cohort. Publicly available summary-level or de-identified datasets were analyzed, including FinnGen sepsis GWAS data (GWAS ID: finn-b-O15_PUERP_SEPSIS), OneK1K sc-eQTL data, bulk transcriptomic data (GSE65682), and scRNA-seq datasets (GSE167363 and GSE151263). For prospective validation, 30 consecutive adult patients admitted to the intensive care unit who fulfilled the Sepsis-3 criteria were enrolled at the Affiliated Jiangyin Hospital of Nantong University between January 2026 and April 2026. Peripheral blood was collected within 24 hours after fulfillment of the Sepsis-3 criteria. TYMP concentrations in plasma were quantified using ELISA.

TYMP showed a nominal inverse association with sepsis susceptibility in CD4 effector memory/TEMRA cells (OR = 0.644, P = 0.008) in the exploratory MR screening, while genetic colocalization suggested a shared genetic signal with sepsis susceptibility (PPH4 = 0.78). In an independent cohort of 30 patients with sepsis, plasma TYMP levels were significantly elevated in survivors than in non-survivors (124.9 ± 20.7 vs 109.6 ± 15.1 pg/mL, P = 0.033). TYMP exhibited prognostic value for 28-day mortality (AUC = 0.701, P = 0.042), and elevated TYMP expression was associated with improved survival (HR = 0.259, P = 0.029). Single-cell and pseudotime analyses associated TYMP-expressing CD4⁺T cells with immunoregulatory transcriptional programs involving hypoxia and TGFB1 signaling. Pseudotime analysis demonstrated dynamic transcriptional reprogramming toward an immunoregulatory state.

Integrated genetic, transcriptomic, single-cell, and clinical analyses nominate TYMP as a genetically supported candidate protective immunoregulatory marker associated with CD4⁺T cells in sepsis.