Identification of macrophage polarization-related genes for esophageal cancer risk: a multi-omics Mendelian...

This study aims to identify macrophage polarization (MP)-related genes implicated in esophageal cancer (EC) by integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) data with EC genome-wide association study (GWAS) data.

GWAS data were obtained from the UK Biobank for discovery and the FinnGen R10 release for validation. Blood-based mQTL, eQTL, and pQTL summary data were sourced from large European cohorts. Summary Data-based Mendelian Randomization (SMR) analysis assessed the associations between MP-related gene methylation, expression, protein abundance, and EC risk. Colocalization analysis identified shared causal variants.

SMR and colocalization analysis identified 54 methylation loci, seven genes, and one protein associated with EC risk. Based on multi-omics integration and tiered evidence, LEP was classified as tier 1 due to its significant negative association in integrated mQTL-eQTL data. LEP (cg13454199) methylation showed a positive association with EC risk, while LEP expression was negatively associated, indicating that increased LEP methylation may downregulate its expression, potentially raising EC risk. INPP5D and PGF were tier 2 genes due to their associations with EC risk at both methylation and expression levels, with strong colocalization (PPH4 > 0.5). Tier 3 genes SPP1 and USP18 were associated with EC risk at single regulatory levels (protein and methylation, respectively) in the discovery cohort, with colocalization evidence and validation in an independent dataset, respectively.

We identified LEP, INPP5D, PGF, SPP1, and USP18 as key MP-related genes associated with EC risk, providing potential therapeutic targets for EC.

Not applicable.