A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma
Background: Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targ...
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Elsevier
2024-12-01
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| Series: | World Allergy Organization Journal |
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| author | Jia Wang, MD Jinxin Hu, MS Dan Qin, MD Dan Han, MD Jiapeng Hu, MD |
| author_facet | Jia Wang, MD Jinxin Hu, MS Dan Qin, MD Dan Han, MD Jiapeng Hu, MD |
| author_sort | Jia Wang, MD |
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| description | Background: Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment. Methods: Using the GEO dataset, we screened differentially expressed genes (DEGs) in asthma patients' blood. Employing Summary Data-based Mendelian Randomization (SMR) and Two-Sample Mendelian Randomization (TSMR), we pinpointed asthma causal genes, causal DNA methylation sites, and methylation sites affecting gene expression, cross validated with at least 2 large-scale GWAS from each source. We utilized colocalization for genetic associations, meta-analysis for data integration, two-step MR for methylation-gene-asthma mediation mechanism. Druggability was evaluated using Open Target, virtual screening, and docking. Results: Among the 954 DEGs found in asthma patients' blood, increased expression of CEP95 (discovery, OR_SMR = 0.94, 95% CI: 0.91–0.97), RBM6 (discovery, OR_SMR = 0.97, 95% CI: 0.95–0.99), and ITPKB (discovery, OR_SMR = 0.82, 95% CI: 0.74–0.92) in the blood decreased the risk of asthma, higher levels of HOXB-AS1 (discovery, OR_SMR = 1.05, 95% CI: 1.03–1.07), ETS1 (discovery, OR_SMR = 1.62, 95% CI: 1.29–2.04), and JAK2 (discovery, OR_SMR = 1.13, 95% CI: 1.06–1.21) in the blood increased the risk of asthma. Additionally, a total of 8 methylation sites on ITPKB, ETS1, and JAK2 were identified to influence asthma. An increase in methylation at site cg16265553 raised the risk of asthma partially by suppressing ITPKB expression. Similarly, increased methylation at cg13661497 reduced the asthma risk totally by suppressing JAK2 expression. The impact of CEP95, HOXB-AS1, and RBM6 expressions on asthma was further confirmed in lung tissues. Except for HOXB-AS1, all the other genes were potential druggable targets. Conclusion: Our study highlighted that specific gene expressions and methylation sites significantly influence asthma risk and revealed a potential methylation-to-gene-to-asthma mechanism. This provided pivotal evidence for future targeted functional studies and the development of preventive and treatment strategies. |
| format | Article |
| id | doaj-art-e6a45a5b58d344a59f1bd71b890a8da8 |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| spelling | doaj-art-e6a45a5b58d344a59f1bd71b890a8da82024-12-13T10:57:08ZengElsevierWorld Allergy Organization Journal1939-45512024-12-011712101008A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthmaJia Wang, MD0Jinxin Hu, MS1Dan Qin, MD2Dan Han, MD3Jiapeng Hu, MD4Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, ChinaResearch Center of Traditional Chinese Medicine Information Engineering, Beijing University of Chinese Medicine, Beijing, ChinaDepartment of Neonatology, The First Hospital of China Medical University, Shenyang, ChinaDepartment of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China; Corresponding author.Background: Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment. Methods: Using the GEO dataset, we screened differentially expressed genes (DEGs) in asthma patients' blood. Employing Summary Data-based Mendelian Randomization (SMR) and Two-Sample Mendelian Randomization (TSMR), we pinpointed asthma causal genes, causal DNA methylation sites, and methylation sites affecting gene expression, cross validated with at least 2 large-scale GWAS from each source. We utilized colocalization for genetic associations, meta-analysis for data integration, two-step MR for methylation-gene-asthma mediation mechanism. Druggability was evaluated using Open Target, virtual screening, and docking. Results: Among the 954 DEGs found in asthma patients' blood, increased expression of CEP95 (discovery, OR_SMR = 0.94, 95% CI: 0.91–0.97), RBM6 (discovery, OR_SMR = 0.97, 95% CI: 0.95–0.99), and ITPKB (discovery, OR_SMR = 0.82, 95% CI: 0.74–0.92) in the blood decreased the risk of asthma, higher levels of HOXB-AS1 (discovery, OR_SMR = 1.05, 95% CI: 1.03–1.07), ETS1 (discovery, OR_SMR = 1.62, 95% CI: 1.29–2.04), and JAK2 (discovery, OR_SMR = 1.13, 95% CI: 1.06–1.21) in the blood increased the risk of asthma. Additionally, a total of 8 methylation sites on ITPKB, ETS1, and JAK2 were identified to influence asthma. An increase in methylation at site cg16265553 raised the risk of asthma partially by suppressing ITPKB expression. Similarly, increased methylation at cg13661497 reduced the asthma risk totally by suppressing JAK2 expression. The impact of CEP95, HOXB-AS1, and RBM6 expressions on asthma was further confirmed in lung tissues. Except for HOXB-AS1, all the other genes were potential druggable targets. Conclusion: Our study highlighted that specific gene expressions and methylation sites significantly influence asthma risk and revealed a potential methylation-to-gene-to-asthma mechanism. This provided pivotal evidence for future targeted functional studies and the development of preventive and treatment strategies.http://www.sciencedirect.com/science/article/pii/S1939455124001406AsthmaMendelian randomizationGene expressionDNA methylationMediation analysis |
| spellingShingle | Jia Wang, MD Jinxin Hu, MS Dan Qin, MD Dan Han, MD Jiapeng Hu, MD A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma World Allergy Organization Journal Asthma Mendelian randomization Gene expression DNA methylation Mediation analysis |
| title | A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma |
| title_full | A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma |
| title_fullStr | A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma |
| title_full_unstemmed | A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma |
| title_short | A multi-omics Mendelian randomization identifies putatively causal genes and DNA methylation sites for asthma |
| title_sort | multi omics mendelian randomization identifies putatively causal genes and dna methylation sites for asthma |
| topic | Asthma Mendelian randomization Gene expression DNA methylation Mediation analysis |
| url | http://www.sciencedirect.com/science/article/pii/S1939455124001406 |
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