Multi-Omics Prioritization and Clinical Evaluation of CYP4V2 as a Candidate Biomarker in Venous Thromboembolism

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, has a substantial genetic component, but the effector genes and clinically relevant biomarkers remain incompletely defined.

We analyzed FinnGen R12 genome-wide association study (GWAS) summary statistics for VTE and its subphenotypes. The Mixture model for estimating polygenicity and discoverability (MiXeR) was used to characterize the shared genetic architecture between deep vein thrombosis and pulmonary embolism. Cross-tissue Unified Test for Molecular SignaTures (UTMOST) and single-tissue Functional Summary-based Imputation (FUSION) transcriptome-wide association analyses were integrated with Multi-marker Analysis of GenoMic Annotation (MAGMA) gene and pathway analyses to prioritize candidate genes. FUSION conditional and joint analysis was applied to evaluate locus-level independence. Single-variant cis-expression quantitative trait locus (cis-eQTL)-based Mendelian randomization (MR) with Steiger directionality testing was performed for CYP4V2. External validation included GSE48000 whole-blood expression analysis, Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) immune deconvolution, and serum CYP4V2 measurement by enzyme-linked immunosorbent assay (ELISA) in an independent clinical cohort.

MiXeR indicated extensive shared polygenicity between deep vein thrombosis and pulmonary embolism. Across UTMOST, FUSION, and MAGMA, CYP4V2 emerged as the only consensus candidate gene for VTE and its subphenotypes. FUSION conditional analysis supported locus-level prioritization. Single-variant cis-eQTL-based MR showed directionally consistent associations between genetically proxied higher CYP4V2 expression and lower risks of VTE, deep vein thrombosis, and pulmonary embolism. However, regional colocalization did not support a shared CYP4V2 expression-outcome causal variant. In GSE48000, CYP4V2 expression differed between controls and study-defined recurrence-risk phenotypes and was associated with myeloid-cell composition. Serum CYP4V2 levels were lower in patients with VTE than in non-VTE controls.

Integrated gene-prioritization analyses and preliminary transcriptomic and serum-protein associations nominate CYP4V2 for further evaluation as a VTE-associated candidate biomarker. Colocalization does not establish expression-mediated causality. Larger prospective studies and functional validation are required to determine its biological relevance and clinical utility.