DNA Methylation–Mediated Downregulation of SDK1 Promotes COPD Progression: A Multi-Omics Mendelian Randomization Study

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 workCorrespondence: 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 [email protected] 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 [email protected]: 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