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Druggable genome-wide Mendelian randomization integrating GWAS and eQTL/pQTL data identifies targets for lung
Shizhao Cheng1,2, Hao Zhang2, Zhenliang Shi2
1Clinical School of Thoracic, Tianjin Medical University, Tianjin, China.
Abstract:
Lung squamous cell carcinoma (LUSC) is one of the most common types of non-small cell lung cancer with poor prognosis. Druggable genome-wide Mendelian randomization (MR) was conducted to discover LUSC-related targets using expression quantitative trait loci (eQTL) and protein QTL (pQTL) in the ieu_b_4953 dataset and finngen dataset. Bayesian co-localization analysis, summary‑data‑based MR (SMR) analysis, and HEIDI test were conducted to verify the causal associations between genes and LUSC risk. Prediction of prognosis and immune infiltration was performed at the transcriptomic level, and expression patterns of genes were analyzed at the single-cell level. We identified DNMT1, ACSS2, YBX1, SELENOS, PPARA, MST1, CPA4, and MPO as LUSC-related genes based on MR analysis. Although Bayesian co-localization analysis showed negative co-localization results (PPH3 + PPH4 < 0.8), positive SMR (p < 0.05) and HEIDI (p > 0.05) were found in the ieu_b_4953 dataset and finngen dataset. Blood CPA4 and DNMT1 might be protective factors for bladder cancer and allergic rhinitis, respectively. Patients with low expression of CPA4, DNMT1 and YBX1 had better prognosis, while patients with high expression of MST1 had better prognosis. Tumor samples exhibited reduced infiltration of CD4 cells, CD8 cells, activated dendritic cells, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, and mast cells. At the single-cell level, DNMT1, SELENOS and YBX1 were highly expressed in endothelial cells, epithelial cells, fibroblasts, hepatocytes, mast cells, and monocytes/macrophages. MST1 was overexpressed in hepatocytes. This study might deepen the understanding of the LUSC pathogenesis and identify potential targets for the management of LUSC.
Insights
This study used Mendelian randomization to identify potential therapeutic targets for lung squamous cell carcinoma (LUSC). Several genes, including DNMT1 and MST1, were linked to LUSC risk and patient prognosis, offering new avenues for LUSC management.
Area of Science:
- Genetics
- Oncology
- Bioinformatics
Background:
- Lung squamous cell carcinoma (LUSC) presents a significant clinical challenge due to its poor prognosis.
- Identifying novel therapeutic targets is crucial for improving patient outcomes in LUSC.
Purpose of the Study:
- To discover druggable genetic targets associated with lung squamous cell carcinoma (LUSC) risk using genome-wide Mendelian randomization (MR).
- To investigate the prognostic value and immune infiltration patterns related to identified LUSC-associated genes.
- To analyze gene expression at the single-cell level for a deeper understanding of LUSC pathogenesis.
Main Methods:
- Genome-wide Mendelian randomization (MR) analysis utilizing expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) data from the ieu_b_4953 and finngen datasets.
- Bayesian co-localization, summary-data-based MR (SMR), and HEIDI analyses were employed to confirm causal associations.
- Prognostic prediction and immune cell infiltration analysis were conducted at the transcriptomic level, complemented by single-cell expression profiling.
Main Results:
- Eight genes (DNMT1, ACSS2, YBX1, SELENOS, PPARA, MST1, CPA4, MPO) were identified as potentially related to LUSC risk via MR analysis.
- While Bayesian co-localization yielded negative results, SMR and HEIDI analyses supported associations in the analyzed datasets.
- Low expression of CPA4, DNMT1, and YBX1 correlated with better prognosis, whereas high MST1 expression indicated a better prognosis. Significant alterations in immune cell infiltration were observed.
Conclusions:
- The study identified several candidate genes, including DNMT1, MST1, and YBX1, implicated in LUSC pathogenesis and prognosis.
- These findings may contribute to a better understanding of LUSC and suggest potential therapeutic targets for clinical management.
- Further research into the identified genes could pave the way for novel LUSC treatment strategies.
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