Multi-Omics Integration and Proteomic Annotation Prioritize FAM174BAssociated Monocyte Remodeling in COPD and Lung Adenocarcinoma.
TL;DR
Findings suggest that FAM174B-associated monocyte remodeling may represent a candidate biological context linking COPD-related inflammatory remodeling with LUAD-associated tumor microenvironmental change.
Abstract
INTRODUCTION/
Background
Chronic obstructive pulmonary disease (COPD) is associated with increased lung adenocarcinoma (LUAD) risk, but the cellular and molecular programs linking chronic inflammatory remodeling to malignancy remain incompletely defined. Transcriptomic overlap alone cannot distinguish potential upstream contributors from downstream remodeling events.
Materials And Methods
We integrated lung single-cell RNA sequencing datasets from COPD (GSE196638) and LUAD (GSE131907) with two-sample Mendelian randomization (MR) to prioritize shared genes with supportive genetic evidence. Cell-type-resolved transcriptional signatures were identified and intersected across diseases. Shared candidates were screened using cis-eQTL instruments from eQTLGen and GWAS summary statistics for COPD and LUAD. FAM174B protein expression was further examined using publicly available Human Protein Atlas immunohistochemistry data with the anti-FAM174B antibody HPA015306.
Results
Intersection analysis identified 484 shared genes enriched in cytoskeletal organization and cell-substrate adhesion. Exploratory MR screening prioritized FAM174B as a leading shared candidate with nominal risk-increasing estimates for COPD (OR = 1.094, 95% CI: 1.009-1.186) and LUAD (OR = 1.196, 95% CI: 1.026-1.395). These estimates should be interpreted as supportive genetic prioritization rather than definitive causal proof, because formal multiple-testing correction and colocalization were not performed. Human Protein Atlas immunohistochemistry showed low FAM174B staining in normal lung tissue and higher staining in lung adenocarcinoma tissue, supporting disease-associated protein expression but not establishing the cellular source within tumor tissue. Single-cell analyses localized FAM174B expression to immune compartments, including monocytes, and ligand-receptor inference suggested LUAD-associated monocyte signaling shifts involving adhesion- and matrix-associated pathways.
Discussion
These findings suggest that FAM174B-associated monocyte remodeling may represent a candidate biological context linking COPD-related inflammatory remodeling with LUAD-associated tumor microenvironmental change. However, the evidence remains hypothesis-generating, as the MR analysis was exploratory, the single-cell comparisons were not donor-aware, and protein-level evidence was based on public representative immunohistochemistry images.
Conclusion
This integrative analysis prioritizes FAM174B as a shared COPD-LUAD candidate with supportive genetic, single-cell, and protein-level evidence. Experimental validation, colocalization, donor-aware single-cell analysis, and cell-type-resolved protein confirmation are needed before a causal or therapeutic role can be established.