Defining the relationship between cathepsin B and esophageal adenocarcinoma: conjoint analysis of Mendelian randomization, transcriptome-wide association studies, and single-cell RNA sequencing data
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| Main Authors: | , , , , , , |
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| Format: | Preprint |
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2025
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| _version_ | 1866908295995850752 |
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| author | Li, Jialin Yang, Shaokang Gao, Xinliang Tang, Mingbo Ma, Xiaobo Tian, Suyan Liu, Wei |
| author_facet | Li, Jialin Yang, Shaokang Gao, Xinliang Tang, Mingbo Ma, Xiaobo Tian, Suyan Liu, Wei |
| contents | Background: Esophageal cancer poses a significant global health challenge, with the incidence of esophageal adenocarcinoma (EAC), a predominant subtype, increasing notably in Western countries. Cathepsins, a family of lysosomal proteolytic enzymes, have been implicated in the progression of various tumors. However, the causal relationship between the cathepsin family and EAC remains unresolved. Methods: To evaluate these potential causal associations, integrative analyses were conducted, integrating Mendelian randomization (MR), transcriptome-wide association study (TWAS), single-cell RNA sequencing (scRNA-seq), and single-cell expression quantitative trait locus (sc-eQTL) analyses. Results: Univariable and multivariable MR analyses demonstrated that elevated levels of cathepsin B (CTSB) were associated with a reduced risk of EAC. The TWAS analysis identified a negative association between CTSB expression in esophageal tissue and EAC, consistent with experimental validation using immunohistochemistry. The scRNA-seq data analysis indicated that CTSB expression was predominantly localized in macrophages infiltrating EAC. Colocalization analysis incorporating sc-eQTL data specific to macrophages confirmed a shared causal variant between CTSB and macrophages. Additionally, MR analysis of CTSB and macrophage scavenger receptor (MSR) types I and II established their interrelationship, suggesting that CTSB may influence the proinflammatory phenotype of macrophages, ultimately affecting EAC risk. Conclusions: This integrative analysis, utilizing MR, TWAS, scRNA-seq, and sc-eQTL data, identified a significant causal association between CTSB and EAC, potentially mediated through macrophage MSR regulation. These findings suggest that targeting cathepsin B could represent a novel strategy for the diagnosis and treatment of EAC. |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2504_01270 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Defining the relationship between cathepsin B and esophageal adenocarcinoma: conjoint analysis of Mendelian randomization, transcriptome-wide association studies, and single-cell RNA sequencing data Li, Jialin Yang, Shaokang Gao, Xinliang Tang, Mingbo Ma, Xiaobo Tian, Suyan Liu, Wei Tissues and Organs Genomics Background: Esophageal cancer poses a significant global health challenge, with the incidence of esophageal adenocarcinoma (EAC), a predominant subtype, increasing notably in Western countries. Cathepsins, a family of lysosomal proteolytic enzymes, have been implicated in the progression of various tumors. However, the causal relationship between the cathepsin family and EAC remains unresolved. Methods: To evaluate these potential causal associations, integrative analyses were conducted, integrating Mendelian randomization (MR), transcriptome-wide association study (TWAS), single-cell RNA sequencing (scRNA-seq), and single-cell expression quantitative trait locus (sc-eQTL) analyses. Results: Univariable and multivariable MR analyses demonstrated that elevated levels of cathepsin B (CTSB) were associated with a reduced risk of EAC. The TWAS analysis identified a negative association between CTSB expression in esophageal tissue and EAC, consistent with experimental validation using immunohistochemistry. The scRNA-seq data analysis indicated that CTSB expression was predominantly localized in macrophages infiltrating EAC. Colocalization analysis incorporating sc-eQTL data specific to macrophages confirmed a shared causal variant between CTSB and macrophages. Additionally, MR analysis of CTSB and macrophage scavenger receptor (MSR) types I and II established their interrelationship, suggesting that CTSB may influence the proinflammatory phenotype of macrophages, ultimately affecting EAC risk. Conclusions: This integrative analysis, utilizing MR, TWAS, scRNA-seq, and sc-eQTL data, identified a significant causal association between CTSB and EAC, potentially mediated through macrophage MSR regulation. These findings suggest that targeting cathepsin B could represent a novel strategy for the diagnosis and treatment of EAC. |
| title | Defining the relationship between cathepsin B and esophageal adenocarcinoma: conjoint analysis of Mendelian randomization, transcriptome-wide association studies, and single-cell RNA sequencing data |
| topic | Tissues and Organs Genomics |
| url | https://arxiv.org/abs/2504.01270 |