# Causal Associations Between Cystatin and Lung Cancer: A Two‐Sample Mendelian Randomization Study

## TL;DR

This study finds a causal link between Cystatin 8 and squamous cell lung carcinoma, and Cystatin D and lung adenocarcinoma, using genetic data.

## Contribution

The study identifies specific causal associations between cystatins and lung cancer subtypes using Mendelian randomization.

## Key findings

- Genetically predicted Cystatin 8 is causally linked to squamous cell lung carcinoma.
- Cystatin D shows a significant association with lung adenocarcinoma after outlier removal.
- Cystatins may have distinct roles in different lung cancer subtypes.

## Abstract

The cystatin family is particularly relevant in lung cancer research due to its links to inflammation, protease balance, and tumor progression. Although population‐based studies have documented associations between cystatin and lung cancer, causal relationships remain undetermined.

Based on genomic statistics of seven different cystatins and three subtypes of lung cancer, we conducted a two‐sample Mendelian randomization (MR) study. The inverse‐variance weighted (IVW) method was the main approach for causality estimation. The weighted median, simple mode, weighted mode, and MR‐Egger regression methods were further employed to validate the main findings. In the sensitivity analysis, horizontal pleiotropy was assessed by MR‐Egger regression and Cochran’s Q test. MR‐PRESSO and Radial MR methods were used to identify heterogeneity and remove outliers.

Genetically predicted Cystatin 8 was causally associated with squamous cell lung carcinoma (OR = 1.062, 95% CI: 1.004–1.124, p = 0.035). No causal relationships were found for genetically predicted cystatin 8, ‐B, ‐D, ‐F, or ‐M with squamous cell lung carcinoma, lung adenocarcinoma, and NSCLC. However, outliers were identified between Cystatin D, ‐M, and ‐F using MR‐PRESSO and Radial MR. After the removal of outliers, the association between Cystatin D and lung adenocarcinoma turned significant (OR = 1.178, 95% CI: 1.023–1.358, p = 0.023). Sensitivity analyses confirmed the robustness of main results after outliers removal.

Genetically predicted Cystatin 8 was causally associated with squamous cell lung carcinoma. Future population‐based studies are required to substantiate these results.

This Mendelian randomization study revealed a causal association between genetically predicted cystatin 8 and squamous cell lung carcinoma, while Cystatin D was linked to lung adenocarcinoma after outlier adjustment. The findings suggest cystatins may play distinct roles in lung cancer subtypes, calling for further investigation to confirm these relationships.