Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease

Zihui Wang; Shaoqiang Li; Guannan Cai; Yuan Gao; Huajing Yang; Yun Li; Juncheng Liang; Shiyu Zhang; Jieying Hu; Jinping Zheng

doi:10.3389/fcimb.2024.1386506

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease

Front Cell Infect Microbiol. 2024 Apr 10:14:1386506. doi: 10.3389/fcimb.2024.1386506. eCollection 2024.

Authors

Zihui Wang^#¹, Shaoqiang Li^#¹, Guannan Cai^#¹, Yuan Gao¹, Huajing Yang¹, Yun Li¹, Juncheng Liang¹, Shiyu Zhang¹, Jieying Hu¹, Jinping Zheng¹

Affiliation

¹ National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

^# Contributed equally.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD.

Methods: Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases.

Results: A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV₁.

Conclusions: Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.

Keywords: Mendelian randomization; chronic obstructive pulmonary disease; druggable genes; drugs repurposing; lung function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Repositioning*
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Mendelian Randomization Analysis*
Polymorphism, Single Nucleotide
Pulmonary Disease, Chronic Obstructive* / drug therapy
Pulmonary Disease, Chronic Obstructive* / genetics
Pulmonary Disease, Chronic Obstructive* / physiopathology
Quantitative Trait Loci*

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was sponsored by the Foundation of Guangzhou National Laboratory (SRPG22 018, SRPG22 016) and Guangzhou Science and Technology Plans (No. 202201020513). However, study funding had no influence on the study.