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已发表论文
DNA 甲基化介导的 SDK1 表达下调促进慢性阻塞性肺疾病进展：一项多组学孟德尔随机化研究
Authors Xue Z , Xue Q, Deng X, Li S, Liang P, Chen H, Xue H, Fang G
Received 14 April 2025
Accepted for publication 5 October 2025
Published 15 October 2025 Volume 2025:20 Pages 3387—3397
DOI https://doi.org/10.2147/COPD.S534335
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Richard Russell
Zhichun Xue,1,2,* Qing Xue,1,2,* Xinyu Deng,1,2 Shuqi Li,1,2 Peng Liang,1,2 Huiling Chen,3 Hong Xue,4– 6 Guiju Fang1,2
1Department of Respiratory and Critical Care Medicine, Ningde Clinical Medical College of Fujian Medical University, Ningde, Fujian, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Ningde Municipal Hospital of Ningde Normal University, Ningde, Fujian, People’s Republic of China; 3College of Marine Sciences, Ningde Normal University, Ningde, Fujian, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, Fujian, People’s Republic of China; 6Chest Medical Center, Fujian Provincial Hospital; Fujian Provincial Research Laboratory of Respiratory Diseases, Fuzhou, Fujian, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guiju Fang, Department of Respiratory and Critical Care Medicine, Ningde Clinical Medical College of Fujian Medical University, Ningde, Fujian, People’s Republic of China, Email fangguiju2@163.com Hong Xue, Department of Respiratory and Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Email xuehongfjsl@fjmu.edu.cn
Purpose: To systematically explore the potential causal relationships among gene expression, DNA methylation, and chronic obstructive pulmonary disease (COPD) susceptibility using a multi-omics Mendelian randomization (MR) framework, and to further investigate key regulatory genes and methylation sites potentially involved in COPD pathogenesis.
Patients and Methods: We integrated genome-wide association study (GWAS) data from 635,145 individuals, expression quantitative trait loci (eQTL) data (N=15,695) from the eQTLGen Consortium, and methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). Two-sample Mendelian randomization was performed using genome-wide significant, linkage disequilibrium (LD)-independent (P < 5× 10−⁸, r² < 0.1) instruments filtered by Steiger analysis. Sensitivity analyses included inverse-variance weighted (IVW), MR-Egger, weighted median, and leave-one-out approaches. Colocalization analysis (posterior probability H₄ ≥ 0.75) and summary data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) test (P > 0.05) were used to validate shared causal variants. A three-step Mendelian randomization assessed mediation through methylation, gene expression, and COPD risk.
Results: We identified eight putative causal genes for COPD based on Mendelian randomization and colocalization analyses. SDK1 demonstrated consistent statistical significance across all subsequent steps. Increased SDK1 expression was significantly associated with a reduced risk of COPD (β = – 0.124, P = 0.002). Methylation at the intronic CpG site cg07526904 within SDK1 was associated with lower SDK1 expression (β = – 0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038). Mediation analysis indicated that SDK1 expression mediated approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038), supporting a potential epigenetic pathway.
Conclusion: This analysis suggests that SDK1 methylation may affect COPD risk by regulating gene expression, highlighting a potential epigenetic mechanism. These findings offer preliminary insights into COPD pathogenesis and may help identify targets for future biomarker-based interventions.
Keywords: chronic obstructive pulmonary disease, COPD, SDK1, DNA methylation, gene expression, Mendelian randomization
1Department of Respiratory and Critical Care Medicine, Ningde Clinical Medical College of Fujian Medical University, Ningde, Fujian, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Ningde Municipal Hospital of Ningde Normal University, Ningde, Fujian, People’s Republic of China; 3College of Marine Sciences, Ningde Normal University, Ningde, Fujian, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, Fujian, People’s Republic of China; 6Chest Medical Center, Fujian Provincial Hospital; Fujian Provincial Research Laboratory of Respiratory Diseases, Fuzhou, Fujian, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guiju Fang, Department of Respiratory and Critical Care Medicine, Ningde Clinical Medical College of Fujian Medical University, Ningde, Fujian, People’s Republic of China, Email fangguiju2@163.com Hong Xue, Department of Respiratory and Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Email xuehongfjsl@fjmu.edu.cn
Purpose: To systematically explore the potential causal relationships among gene expression, DNA methylation, and chronic obstructive pulmonary disease (COPD) susceptibility using a multi-omics Mendelian randomization (MR) framework, and to further investigate key regulatory genes and methylation sites potentially involved in COPD pathogenesis.
Patients and Methods: We integrated genome-wide association study (GWAS) data from 635,145 individuals, expression quantitative trait loci (eQTL) data (N=15,695) from the eQTLGen Consortium, and methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). Two-sample Mendelian randomization was performed using genome-wide significant, linkage disequilibrium (LD)-independent (P < 5× 10−⁸, r² < 0.1) instruments filtered by Steiger analysis. Sensitivity analyses included inverse-variance weighted (IVW), MR-Egger, weighted median, and leave-one-out approaches. Colocalization analysis (posterior probability H₄ ≥ 0.75) and summary data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) test (P > 0.05) were used to validate shared causal variants. A three-step Mendelian randomization assessed mediation through methylation, gene expression, and COPD risk.
Results: We identified eight putative causal genes for COPD based on Mendelian randomization and colocalization analyses. SDK1 demonstrated consistent statistical significance across all subsequent steps. Increased SDK1 expression was significantly associated with a reduced risk of COPD (β = – 0.124, P = 0.002). Methylation at the intronic CpG site cg07526904 within SDK1 was associated with lower SDK1 expression (β = – 0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038). Mediation analysis indicated that SDK1 expression mediated approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038), supporting a potential epigenetic pathway.
Conclusion: This analysis suggests that SDK1 methylation may affect COPD risk by regulating gene expression, highlighting a potential epigenetic mechanism. These findings offer preliminary insights into COPD pathogenesis and may help identify targets for future biomarker-based interventions.
Keywords: chronic obstructive pulmonary disease, COPD, SDK1, DNA methylation, gene expression, Mendelian randomization