Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis
The genome-wide association studies (GWAS) of lung disease and lung function indices suffer from challenges to be transformed into clinical interventions, due to a lack of knowledge on the molecular mechanism underlying the GWAS associations. A proteome-wide association study (PWAS) was first perfor...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/47/3/167 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850089390207926272 |
|---|---|
| author | Yansong Zhao Lujia Shen Ran Yan Lu Liu Ping Guo Shuai Liu Yingxuan Chen Zhongshang Yuan Weiming Gong Jiadong Ji |
| author_facet | Yansong Zhao Lujia Shen Ran Yan Lu Liu Ping Guo Shuai Liu Yingxuan Chen Zhongshang Yuan Weiming Gong Jiadong Ji |
| author_sort | Yansong Zhao |
| collection | DOAJ |
| description | The genome-wide association studies (GWAS) of lung disease and lung function indices suffer from challenges to be transformed into clinical interventions, due to a lack of knowledge on the molecular mechanism underlying the GWAS associations. A proteome-wide association study (PWAS) was first performed to identify candidate proteins by integrating two independent largest protein quantitative trait loci datasets of plasma proteins and four large-scale GWAS summary statistics of lung function indices (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and peak expiratory flow (PEF)), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, with a discovery dataset, we conducted Mendelian randomization (MR) and Bayesian colocalization analyses to select potentially causal proteins, followed by a replicated MR analysis with an independent dataset. Mediation analysis was also performed to explore the possible mediating role of these indices on the association between proteins and two common lung diseases (chronic obstructive pulmonary disease, COPD and Asthma). We finally prioritized the potential drug targets. A total of 210 protein–lung function index associations were identified by PWAS, and were significantly enriched in the pulmonary fibrosis and lung tissue repair. Subsequent MR and colocalization analysis identified 59 causal protein-index pairs, among which 42 pairs were replicated. Further mediation analysis identified 3 potential pathways from proteins to COPD or asthma mediated by FEV1/FVC. The mediated proportion ranges from 68.4% to 82.7%. Notably, 24 proteins were reported as druggable targets in Drug Gene Interaction Database, among which 8 were reported to interact with drugs, including <i>FKBP4</i>, <i>GM2A</i>, <i>COL6A3</i>, <i>MAPK3</i>, <i>SERPING1</i>, <i>XPNPEP1</i>, <i>DNER</i>, and <i>FER</i>. Our study identified the crucial plasma proteins causally associated with lung functions and highlighted potential mediating mechanism underlying the effect of proteins on common lung diseases. These findings may have an important insight into pathogenesis and possible future therapies of lung disorders. |
| format | Article |
| id | doaj-art-d516a1a85a704e698b8dc8947cdf86c5 |
| institution | DOAJ |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj-art-d516a1a85a704e698b8dc8947cdf86c52025-08-20T02:42:46ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-03-0147316710.3390/cimb47030167Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration AnalysisYansong Zhao0Lujia Shen1Ran Yan2Lu Liu3Ping Guo4Shuai Liu5Yingxuan Chen6Zhongshang Yuan7Weiming Gong8Jiadong Ji9Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USADepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Wenhua West Road, Jinan 250012, ChinaInstitute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan 250003, ChinaThe genome-wide association studies (GWAS) of lung disease and lung function indices suffer from challenges to be transformed into clinical interventions, due to a lack of knowledge on the molecular mechanism underlying the GWAS associations. A proteome-wide association study (PWAS) was first performed to identify candidate proteins by integrating two independent largest protein quantitative trait loci datasets of plasma proteins and four large-scale GWAS summary statistics of lung function indices (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and peak expiratory flow (PEF)), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, with a discovery dataset, we conducted Mendelian randomization (MR) and Bayesian colocalization analyses to select potentially causal proteins, followed by a replicated MR analysis with an independent dataset. Mediation analysis was also performed to explore the possible mediating role of these indices on the association between proteins and two common lung diseases (chronic obstructive pulmonary disease, COPD and Asthma). We finally prioritized the potential drug targets. A total of 210 protein–lung function index associations were identified by PWAS, and were significantly enriched in the pulmonary fibrosis and lung tissue repair. Subsequent MR and colocalization analysis identified 59 causal protein-index pairs, among which 42 pairs were replicated. Further mediation analysis identified 3 potential pathways from proteins to COPD or asthma mediated by FEV1/FVC. The mediated proportion ranges from 68.4% to 82.7%. Notably, 24 proteins were reported as druggable targets in Drug Gene Interaction Database, among which 8 were reported to interact with drugs, including <i>FKBP4</i>, <i>GM2A</i>, <i>COL6A3</i>, <i>MAPK3</i>, <i>SERPING1</i>, <i>XPNPEP1</i>, <i>DNER</i>, and <i>FER</i>. Our study identified the crucial plasma proteins causally associated with lung functions and highlighted potential mediating mechanism underlying the effect of proteins on common lung diseases. These findings may have an important insight into pathogenesis and possible future therapies of lung disorders.https://www.mdpi.com/1467-3045/47/3/167proteomicsproteome-wide association studytherapeuticlung functionbioinformatics methods |
| spellingShingle | Yansong Zhao Lujia Shen Ran Yan Lu Liu Ping Guo Shuai Liu Yingxuan Chen Zhongshang Yuan Weiming Gong Jiadong Ji Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis Current Issues in Molecular Biology proteomics proteome-wide association study therapeutic lung function bioinformatics methods |
| title | Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis |
| title_full | Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis |
| title_fullStr | Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis |
| title_full_unstemmed | Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis |
| title_short | Identification of Candidate Lung Function-Related Plasma Proteins to Pinpoint Drug Targets for Common Pulmonary Diseases: A Comprehensive Multi-Omics Integration Analysis |
| title_sort | identification of candidate lung function related plasma proteins to pinpoint drug targets for common pulmonary diseases a comprehensive multi omics integration analysis |
| topic | proteomics proteome-wide association study therapeutic lung function bioinformatics methods |
| url | https://www.mdpi.com/1467-3045/47/3/167 |
| work_keys_str_mv | AT yansongzhao identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT lujiashen identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT ranyan identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT luliu identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT pingguo identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT shuailiu identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT yingxuanchen identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT zhongshangyuan identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT weiminggong identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis AT jiadongji identificationofcandidatelungfunctionrelatedplasmaproteinstopinpointdrugtargetsforcommonpulmonarydiseasesacomprehensivemultiomicsintegrationanalysis |