# Multi-Omics and Single-Cell Mendelian Randomization Reveal a Potential Role of VNN2 in Lung Adenocarcinoma in Resting Natural Killer Cells

## TL;DR

Higher VNN2 gene expression is linked to lower lung cancer risk, especially in resting natural killer cells, suggesting a possible role in cancer prevention.

## Contribution

This study identifies a cell-type-specific role of VNN2 in lung adenocarcinoma using multi-omics and single-cell MR analysis.

## Key findings

- Genetically predicted higher VNN2 expression is associated with reduced lung adenocarcinoma risk.
- VNN2 is significantly downregulated in lung tumors compared to normal tissues.
- The strongest association is observed in resting natural killer cells.

## Abstract

We aimed to evaluate the potential association between genetically predicted vanin-2 (VNN2) expression and lung adenocarcinoma (LUAD) risk, and to explore the immune cell subtype that may underlie this relationship.

We integrated whole-blood expression quantitative trait loci (eQTL) data from eQTLGen, plasma protein quantitative trait loci (pQTL) data from deCODE, and LUAD genome-wide association study (GWAS) data from European-ancestry cohorts, together with differential expression analysis using GEPIA2, to identify candidate genes for subsequent single-cell eQTL (sc-eQTL) Mendelian randomization (MR) analysis. For the sc-eQTL analysis, VNN2-associated eQTLs from 14 immune cell types profiled in the OneK1K single-cell eQTL resource were tested for associations with LUAD risk.

Bulk-level MR analysis showed that genetically predicted increases in VNN2 expression and protein levels were significantly associated with a reduced risk of LUAD (eQTL-MR: odds ratio (OR) = 0.964, 95% confidence interval (95% CI), 0.934–0.995; P = 0.024; pQTL-MR: OR = 0.946, 95% CI, 0.921–0.970; P = 2.87 × 10−5). Transcriptomic analyses confirmed significant downregulation of VNN2 in LUAD tumors compared with normal lung tissues. sc-eQTL MR identified the strongest association in resting natural killer (rNK) cells (OR = 0.896, 95% CI, 0.829–0.967; P = 0.005).

Multi-omics and sc-eQTL MR analyses indicated that genetically predicted increases in VNN2 expression were associated with a reduced risk of LUAD, with the most pronounced effect observed in rNK cells. These findings suggest a potential cell type–specific role of VNN2 in LUAD susceptibility and warrant further studies to validate its biological relevance and clinical implications.