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使用孟德尔随机化确定术后腹壁疝的潜在药物靶点：一项多组学研究

Identifying potential drug targets for postoperative abdominal wall hernia using Mendelian randomization: a multi-omics study.

作者信息

Sun Chensong, Liu Ga, Liu Taobin, Gong Haixia

机构信息

Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.

Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.

出版信息

Sci Rep. 2025 Aug 25;15(1):31316. doi: 10.1038/s41598-025-16101-6.

DOI:10.1038/s41598-025-16101-6
PMID:40855105
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12379127/
Abstract

This study aims to identify potential drug targets for postoperative abdominal wall hernia. Mendelian Randomization (MR) was applied to integrate data from druggable gene libraries, cis-pQTL data, and cis-eQTL data to analyze postoperative abdominal wall hernia in the FinnGen R11 population. Sensitivity and heterogeneity tests were conducted, along with reverse causality validation, to explore potential drug targets. A colocalization analysis was performed based on three cis-pQTL databases and cis-eQTL databases. Linkage disequilibrium was verified using Summary Data-Based Mendelian Randomization (SMR), and potential drug side effects were assessed using existing databases. Finally, drug target predictions and molecular docking studies were conducted. MR analysis revealed that, within the druggable target range, only one druggable gene, cathepsin S (CTSS) (FDR < 0.05; OR = 1.13, 95% CI = 1.06-1.20, P = 6.79 × 10e-5), was positively correlated with postoperative abdominal wall hernia. Colocalization analysis showed PPH4 > 0.7 in the cis-pQTL and cis-eQTL gene window of ± 50 kb. A key variant (rs41305070) was identified. Evaluation of drug side effects and molecular docking demonstrated that CTSS holds potential as a promising druggable target. Elevated levels of CTSS increase the risk of postoperative abdominal wall hernia, making CTSS a promising therapeutic target for this condition.

摘要

本研究旨在确定术后腹壁疝的潜在药物靶点。应用孟德尔随机化（MR）整合来自可药物化基因文库、顺式pQTL数据和顺式eQTL数据，以分析FinnGen R11人群中的术后腹壁疝。进行了敏感性和异质性测试以及反向因果关系验证，以探索潜在的药物靶点。基于三个顺式pQTL数据库和顺式eQTL数据库进行了共定位分析。使用基于汇总数据的孟德尔随机化（SMR）验证连锁不平衡，并使用现有数据库评估潜在的药物副作用。最后，进行了药物靶点预测和分子对接研究。MR分析显示，在可药物化靶点范围内，只有一个可药物化基因组织蛋白酶S（CTSS）（FDR < 0.05；OR = 1.13，95%CI = 1.06 - 1.20，P = 6.79 × 10e - 5）与术后腹壁疝呈正相关。共定位分析显示在±50 kb的顺式pQTL和顺式eQTL基因窗口中PPH4 > 0.7。鉴定出一个关键变体（rs41305070）。药物副作用评估和分子对接表明，CTSS有潜力成为一个有前景的可药物化靶点。CTSS水平升高会增加术后腹壁疝的风险，使其成为这种疾病有前景的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/eca19a8b23d7/41598_2025_16101_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/4ec083d697e0/41598_2025_16101_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/13ff558d5c2e/41598_2025_16101_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/05131379f4f6/41598_2025_16101_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/2476561391ab/41598_2025_16101_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/26165a32ec8d/41598_2025_16101_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/eca19a8b23d7/41598_2025_16101_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/4ec083d697e0/41598_2025_16101_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/13ff558d5c2e/41598_2025_16101_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/05131379f4f6/41598_2025_16101_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/2476561391ab/41598_2025_16101_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/26165a32ec8d/41598_2025_16101_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72a9/12379127/eca19a8b23d7/41598_2025_16101_Fig6_HTML.jpg

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本文引用的文献

[1]
IRIS, a randomised, double-blind, placebo-controlled trial of interleukin-6 receptor inhibition undergoing endovascular treatment in acute anterior circulation ischaemic stroke: study rationale and design.

Stroke Vasc Neurol. 2024-11-28

[2]
Causation between the gut microbiota and inguinal hernia: a two-sample double-sided Mendelian randomization study.

Sci Rep. 2024-9-4

[3]
PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.

Stroke Vasc Neurol. 2025-4-29

[4]
Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke.

J Am Heart Assoc. 2024-8-20

[5]
Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine.

J Headache Pain. 2024-7-22

[6]
Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes.

Respir Res. 2024-5-23

[7]
The causal association between body fat distribution and risk of abdominal wall hernia: a two-sample Mendelian randomization study.

Hernia. 2024-4

[8]
Mendelian randomization analyses explore the relationship between cathepsins and lung cancer.

Commun Biol. 2023-10-7

[9]
Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome.

Genome Med. 2023-9-19

[10]
Transcriptome-wide association studies: recent advances in methods, applications and available databases.

Commun Biol. 2023-9-1

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