Identification of potential drug targets for allergic diseases from a genetic perspective: A mendelian randomization study

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy Pub Date : 2024-04-04 DOI:10.1002/clt2.12350

Hui Wang, Jianyu Pang, Yuguan Zhou, Qi Qi, Yuheng Tang, Samina Gul, Miaomiao Sheng, Juhua Dan, Wenru Tang

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Abstract

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.

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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

背景过敏性疾病通常是指一组主要由肥大细胞或嗜酸性粒细胞活化引起的异质性疾病，包括特应性皮炎（AD）、过敏性鼻炎（AR）和哮喘。哮喘、过敏性鼻炎和过敏性皮炎共影响着全球约五分之一的人口，给社会造成了巨大的经济负担。尽管目前已有治疗过敏性疾病的药物，但已证明这些药物不足以控制复发和阻止疾病进展。因此，需要新的药物靶点来预防过敏性疾病的发生。方法我们采用孟德尔随机化方法来确定治疗过敏性疾病的潜在药物靶点。利用最新报道的全基因组关联研究（GWAS）中 1537 种血浆蛋白的 1798 个遗传工具，我们使用孟德尔随机方法分析了 Ferreira MA 等人的 GWAS 统计摘要（nCase = 180,129, nControl = 180,709）。此外，我们还通过 FinnGen 和英国生物库队列的 GWAS 数据验证了我们的研究结果。随后，我们通过反向因果分析、贝叶斯共定位分析和表型扫描进行了敏感性测试。此外，我们还进行了蛋白-蛋白相互作用分析，以确定因果蛋白之间的相互作用。最后，根据潜在的蛋白质靶点，我们进行了分子对接，以确定治疗过敏性疾病的潜在药物。结果在Bonferroni显著性（p < 3.25 × 10-5）下，孟德尔随机分析发现了11对显著相关的蛋白质-过敏性疾病。其中，TNFAIP3、ERBB3、TLR1 和 IL1RL2 蛋白水平的升高与过敏性疾病风险的降低有关，相应的几率比分别为 0.82（0.76-0.88）、0.74（0.66-0.82）、0.49（0.45-0.55）和 0.81（0.75-0.87）。相反，IL6R、IL1R1、ITPKA、IL1RL1、KYNU、LAYN 和 LRP11 蛋白水平的升高与过敏性疾病风险的升高有关，相应的几率比为 1.相应的几率比分别为 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) 和 1.05 (1.03-1.07)。贝叶斯共定位分析表明，LAYN（coloc.abf-PPH4 = 0.819）和 TNFAIP3（coloc.abf-PPH4 = 0.930）具有与过敏性疾病相关的相同变异。结论我们的研究表明 TNFAIP3 和 LAYN 的表达水平与过敏性疾病风险之间存在因果关系，这表明它们是治疗这些疾病的潜在药物靶点，值得进一步临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Allergy Immunology and Microbiology-Immunology

CiteScore

7.50

自引率

4.50%

发文量

117

审稿时长

12 weeks

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.