{"title":"从基因角度识别过敏性疾病的潜在药物靶点:孟德尔随机化研究","authors":"Hui Wang, Jianyu Pang, Yuguan Zhou, Qi Qi, Yuheng Tang, Samina Gul, Miaomiao Sheng, Juhua Dan, Wenru Tang","doi":"10.1002/clt2.12350","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Allergic diseases typically refer to a heterogeneous group of conditions primarily caused by the activation of mast cells or eosinophils, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma. Asthma, AR, and AD collectively affect approximately one-fifth of the global population, imposing a significant economic burden on society. Despite the availability of drugs to treat allergic diseases, they have been shown to be insufficient in controlling relapses and halting disease progression. Therefore, new drug targets are needed to prevent the onset of allergic diseases.</p>\n </section>\n \n <section>\n \n <h3> Method</h3>\n \n <p>We employed a Mendelian randomization approach to identify potential drug targets for the treatment of allergic diseases. Leveraging 1798 genetic instruments for 1537 plasma proteins from the latest reported Genome-Wide Association Studies (GWAS), we analyzed the GWAS summary statistics of Ferreira MA et al. (nCase = 180,129, nControl = 180,709) using the Mendelian randomization method. Furthermore, we validated our findings in the GWAS data from the FinnGen and UK Biobank cohorts. Subsequently, we conducted sensitivity tests through reverse causal analysis, Bayesian colocalization analysis, and phenotype scanning. Additionally, we performed protein-protein interaction analysis to determine the interaction between causal proteins. Finally, based on the potential protein targets, we conducted molecular docking to identify potential drugs for the treatment of allergic diseases.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>At Bonferroni significance (<i>p</i> < 3.25 × 10<sup>−5</sup>), the Mendelian randomization analysis revealed 11 significantly associated protein-allergic disease pairs. Among these, the increased levels of TNFAIP3, ERBB3, TLR1, and IL1RL2 proteins were associated with a reduced risk of allergic diseases, with corresponding odds ratios of 0.82 (0.76–0.88), 0.74 (0.66–0.82), 0.49 (0.45–0.55), and 0.81 (0.75–0.87), respectively. Conversely, increased levels of IL6R, IL1R1, ITPKA, IL1RL1, KYNU, LAYN, and LRP11 proteins were linked to an elevated risk of allergic diseases, with corresponding odds ratios of 1.04 (1.03–1.05), 1.25 (1.18–1.34), 1.48 (1.25–1.75), 1.14 (1.11–1.18), 1.09 (1.05–1.12), 1.96 (1.56–2.47), and 1.05 (1.03–1.07), respectively. Bayesian colocalization analysis suggested that LAYN (coloc.abf-PPH4 = 0.819) and TNFAIP3 (coloc.abf-PPH4 = 0.930) share the same variant associated with allergic diseases.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our study demonstrates a causal association between the expression levels of TNFAIP3 and LAYN and the risk of allergic diseases, suggesting them as potential drug targets for these conditions, warranting further clinical investigation.</p>\n </section>\n </div>","PeriodicalId":10334,"journal":{"name":"Clinical and Translational Allergy","volume":"14 4","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/clt2.12350","citationCount":"0","resultStr":"{\"title\":\"Identification of potential drug targets for allergic diseases from a genetic perspective: A mendelian randomization study\",\"authors\":\"Hui Wang, Jianyu Pang, Yuguan Zhou, Qi Qi, Yuheng Tang, Samina Gul, Miaomiao Sheng, Juhua Dan, Wenru Tang\",\"doi\":\"10.1002/clt2.12350\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Allergic diseases typically refer to a heterogeneous group of conditions primarily caused by the activation of mast cells or eosinophils, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma. Asthma, AR, and AD collectively affect approximately one-fifth of the global population, imposing a significant economic burden on society. Despite the availability of drugs to treat allergic diseases, they have been shown to be insufficient in controlling relapses and halting disease progression. Therefore, new drug targets are needed to prevent the onset of allergic diseases.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Method</h3>\\n \\n <p>We employed a Mendelian randomization approach to identify potential drug targets for the treatment of allergic diseases. Leveraging 1798 genetic instruments for 1537 plasma proteins from the latest reported Genome-Wide Association Studies (GWAS), we analyzed the GWAS summary statistics of Ferreira MA et al. (nCase = 180,129, nControl = 180,709) using the Mendelian randomization method. Furthermore, we validated our findings in the GWAS data from the FinnGen and UK Biobank cohorts. Subsequently, we conducted sensitivity tests through reverse causal analysis, Bayesian colocalization analysis, and phenotype scanning. Additionally, we performed protein-protein interaction analysis to determine the interaction between causal proteins. Finally, based on the potential protein targets, we conducted molecular docking to identify potential drugs for the treatment of allergic diseases.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>At Bonferroni significance (<i>p</i> < 3.25 × 10<sup>−5</sup>), the Mendelian randomization analysis revealed 11 significantly associated protein-allergic disease pairs. Among these, the increased levels of TNFAIP3, ERBB3, TLR1, and IL1RL2 proteins were associated with a reduced risk of allergic diseases, with corresponding odds ratios of 0.82 (0.76–0.88), 0.74 (0.66–0.82), 0.49 (0.45–0.55), and 0.81 (0.75–0.87), respectively. Conversely, increased levels of IL6R, IL1R1, ITPKA, IL1RL1, KYNU, LAYN, and LRP11 proteins were linked to an elevated risk of allergic diseases, with corresponding odds ratios of 1.04 (1.03–1.05), 1.25 (1.18–1.34), 1.48 (1.25–1.75), 1.14 (1.11–1.18), 1.09 (1.05–1.12), 1.96 (1.56–2.47), and 1.05 (1.03–1.07), respectively. Bayesian colocalization analysis suggested that LAYN (coloc.abf-PPH4 = 0.819) and TNFAIP3 (coloc.abf-PPH4 = 0.930) share the same variant associated with allergic diseases.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Our study demonstrates a causal association between the expression levels of TNFAIP3 and LAYN and the risk of allergic diseases, suggesting them as potential drug targets for these conditions, warranting further clinical investigation.</p>\\n </section>\\n </div>\",\"PeriodicalId\":10334,\"journal\":{\"name\":\"Clinical and Translational Allergy\",\"volume\":\"14 4\",\"pages\":\"\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-04-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/clt2.12350\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Allergy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/clt2.12350\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Allergy","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/clt2.12350","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ALLERGY","Score":null,"Total":0}
Identification of potential drug targets for allergic diseases from a genetic perspective: A mendelian randomization study
Background
Allergic diseases typically refer to a heterogeneous group of conditions primarily caused by the activation of mast cells or eosinophils, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma. Asthma, AR, and AD collectively affect approximately one-fifth of the global population, imposing a significant economic burden on society. Despite the availability of drugs to treat allergic diseases, they have been shown to be insufficient in controlling relapses and halting disease progression. Therefore, new drug targets are needed to prevent the onset of allergic diseases.
Method
We employed a Mendelian randomization approach to identify potential drug targets for the treatment of allergic diseases. Leveraging 1798 genetic instruments for 1537 plasma proteins from the latest reported Genome-Wide Association Studies (GWAS), we analyzed the GWAS summary statistics of Ferreira MA et al. (nCase = 180,129, nControl = 180,709) using the Mendelian randomization method. Furthermore, we validated our findings in the GWAS data from the FinnGen and UK Biobank cohorts. Subsequently, we conducted sensitivity tests through reverse causal analysis, Bayesian colocalization analysis, and phenotype scanning. Additionally, we performed protein-protein interaction analysis to determine the interaction between causal proteins. Finally, based on the potential protein targets, we conducted molecular docking to identify potential drugs for the treatment of allergic diseases.
Results
At Bonferroni significance (p < 3.25 × 10−5), the Mendelian randomization analysis revealed 11 significantly associated protein-allergic disease pairs. Among these, the increased levels of TNFAIP3, ERBB3, TLR1, and IL1RL2 proteins were associated with a reduced risk of allergic diseases, with corresponding odds ratios of 0.82 (0.76–0.88), 0.74 (0.66–0.82), 0.49 (0.45–0.55), and 0.81 (0.75–0.87), respectively. Conversely, increased levels of IL6R, IL1R1, ITPKA, IL1RL1, KYNU, LAYN, and LRP11 proteins were linked to an elevated risk of allergic diseases, with corresponding odds ratios of 1.04 (1.03–1.05), 1.25 (1.18–1.34), 1.48 (1.25–1.75), 1.14 (1.11–1.18), 1.09 (1.05–1.12), 1.96 (1.56–2.47), and 1.05 (1.03–1.07), respectively. Bayesian colocalization analysis suggested that LAYN (coloc.abf-PPH4 = 0.819) and TNFAIP3 (coloc.abf-PPH4 = 0.930) share the same variant associated with allergic diseases.
Conclusions
Our study demonstrates a causal association between the expression levels of TNFAIP3 and LAYN and the risk of allergic diseases, suggesting them as potential drug targets for these conditions, warranting further clinical investigation.
期刊介绍:
Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience.
Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.