A multi-omics Mendelian randomization identiﬁes putatively causal genes and DNA methylation sites for asthma

IF 3.9 2区医学 Q2 ALLERGY World Allergy Organization Journal Pub Date : 2024-12-01 DOI:10.1016/j.waojou.2024.101008

Jia Wang MD , Jinxin Hu MS , Dan Qin MD , Dan Han MD , Jiapeng Hu MD

{"title":"A multi-omics Mendelian randomization identiﬁes putatively causal genes and DNA methylation sites for asthma","authors":"Jia Wang MD , Jinxin Hu MS , Dan Qin MD , Dan Han MD , Jiapeng Hu MD","doi":"10.1016/j.waojou.2024.101008","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":54295,"journal":{"name":"World Allergy Organization Journal","volume":"17 12","pages":"Article 101008"},"PeriodicalIF":3.9000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667005/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"World Allergy Organization Journal","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1939455124001406","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ALLERGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

多组学孟德尔随机化鉴定哮喘的推定因果基因和DNA甲基化位点。

背景：哮喘是一种全球性的慢性呼吸系统疾病，发病机制复杂。虽然目前的治疗方法提供了一些缓解，但它们往往不能有效地控制症状和防止许多患者的病情恶化。因此，了解其机制和发现新的药物靶点仍然是更好的治疗的迫切需要。方法：利用GEO数据集筛选哮喘患者血液中的差异表达基因（DEGs）。采用基于汇总数据的孟德尔随机化（SMR）和双样本孟德尔随机化（TSMR），我们确定了哮喘致病基因、致病DNA甲基化位点和影响基因表达的甲基化位点，并与来自每个来源的至少2个大规模GWAS交叉验证。我们利用共定位研究遗传关联，荟萃分析研究数据整合，两步磁共振研究甲基化-基因-哮喘调解机制。通过开放靶标、虚拟筛选和对接来评估药物的可成药性。结果：在哮喘患者血液中发现的954个deg中，CEP95（发现，OR_SMR = 0.94, 95% CI: 0.91 ~ 0.97）、RBM6（发现，OR_SMR = 0.97, 95% CI: 0.95 ~ 0.99）和ITPKB（发现，OR_SMR = 0.82, 95% CI: 0.74 ~ 0.92）的表达增加降低了哮喘的风险，HOXB-AS1（发现，OR_SMR = 1.05, 95% CI: 1.03 ~ 1.07）、ETS1（发现，OR_SMR = 1.62, 95% CI: 1.29 ~ 2.04）和JAK2(发现，OR_SMR = 1.13, 95% CI：1.06-1.21)会增加患哮喘的风险。此外，发现ITPKB、ETS1和JAK2上共有8个甲基化位点影响哮喘。cg16265553位点甲基化的增加部分通过抑制ITPKB表达而增加哮喘的风险。同样，cg13661497位点甲基化的增加完全通过抑制JAK2表达来降低哮喘风险。在肺组织中进一步证实了CEP95、HOXB-AS1和RBM6表达对哮喘的影响。除HOXB-AS1外，其余基因均为潜在的药物靶点。结论：我们的研究强调了特定基因表达和甲基化位点显著影响哮喘风险，并揭示了甲基化-基因-哮喘的潜在机制。这为未来有针对性的功能研究和预防和治疗策略的发展提供了关键证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

World Allergy Organization Journal Immunology and Microbiology-Immunology

CiteScore

9.10

自引率

5.90%

发文量

审稿时长

9 weeks

期刊介绍： The official pubication of the World Allergy Organization, the World Allergy Organization Journal (WAOjournal) publishes original mechanistic, translational, and clinical research on the topics of allergy, asthma, anaphylaxis, and clincial immunology, as well as reviews, guidelines, and position papers that contribute to the improvement of patient care. WAOjournal publishes research on the growth of allergy prevalence within the scope of single countries, country comparisons, and practical global issues and regulations, or threats to the allergy specialty. The Journal invites the submissions of all authors interested in publishing on current global problems in allergy, asthma, anaphylaxis, and immunology. Of particular interest are the immunological consequences of climate change and the subsequent systematic transformations in food habits and their consequences for the allergy/immunology discipline.