解开基因线索：通过孟德尔随机化确定过敏性鼻炎的新治疗靶点。

Unraveling genetic threads: Identifying novel therapeutic targets for allergic rhinitis through Mendelian randomization.

作者信息

Huang Xuerong, Shen Ruoyi, Zheng Zhi

机构信息

Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China.

Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361003, China.

出版信息

World Allergy Organ J. 2024 Jul 1;17(7):100927. doi: 10.1016/j.waojou.2024.100927. eCollection 2024 Jul.

DOI:10.1016/j.waojou.2024.100927

PMID:39040085

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11261789/

Abstract

BACKGROUND

Allergic rhinitis (AR) is a pervasive global health issue, and currently, there is a scarcity of targeted drug therapies available. This study aims to identify potential druggable target genes for AR using Mendelian randomization (MR) analysis.

METHODS

MR analysis was conducted to assess the causal effect of expression quantitative trait loci (eQTL) in the blood on AR. Data on AR were collected from 2 datasets: FinnGen(R9) (11,009 cases and 359,149 controls) and UK Biobank (25,486 cases and 87,097 controls). Colocalization analysis was utilized to assess the common causal genetic variations between the identified drug target genes and AR. We also employed available genome-wide association studies (GWAS) data to gauge the impact of druggable genes on AR biomarkers and other allergic diseases.

RESULTS

This study employs MR to analyze the relationship between 3410 druggable genes and AR. After Bonferroni correction, 10 genes were found to be significantly associated with AR risk (). Colocalization analysis revealed a significant causal relationship between the expression variation of CFL1 and EFEMP2 genes and AR, sharing direct causal variants (colocalization probability PP.H3 + PP.H4 > 0.8), highlighting their importance as potential therapeutic targets for AR. The CFL1 gene showed a causal link with levels of thymic stromal lymphopoietin (TSLP), eosinophil count, and interleukin-13 (IL-13) (, respectively). EFEMP2 was also causally related to eosinophil count, IL-13, and interleukin-17 (IL-17) (, respectively). PheWAS analysis revealed significant associations of CFL1 with asthma, whereas EFEMP2 showed associations with both asthma and eczema. Protein-Protein Interaction (PPI) network analysis further unveiled the direct interactions of EFEMP2 and CFL1 with proteins related to immune regulation and inflammatory responses, with 77.64% of the network consisting of direct bindings, indicating their key roles in modulating AR-related immune and inflammatory responses. Notably, there was an 8.01% significant correlation between immune-related pathways and genes involved in inflammatory responses.

CONCLUSION

These genes present notable associations with AR biomarkers and other autoimmune diseases, offering valuable targets for developing new AR therapies.

摘要

背景

变应性鼻炎（AR）是一个普遍存在的全球健康问题，目前，可用的靶向药物疗法匮乏。本研究旨在使用孟德尔随机化（MR）分析来确定AR潜在的可成药靶基因。

方法

进行MR分析以评估血液中表达数量性状基因座（eQTL）对AR的因果效应。AR数据来自2个数据集：芬兰基因库（R9）（11009例病例和359149例对照）和英国生物银行（25486例病例和87097例对照）。采用共定位分析来评估已鉴定的药物靶基因与AR之间的共同因果遗传变异。我们还利用现有的全基因组关联研究（GWAS）数据来评估可成药基因对AR生物标志物和其他过敏性疾病的影响。

结果

本研究采用MR分析3410个可成药基因与AR之间的关系。经过Bonferroni校正后，发现10个基因与AR风险显著相关（）。共定位分析显示，CFL1和EFEMP2基因的表达变异与AR之间存在显著的因果关系，共享直接因果变异（共定位概率PP.H3 + PP.H4 > 0.8），突出了它们作为AR潜在治疗靶点的重要性。CFL1基因与胸腺基质淋巴细胞生成素（TSLP）水平、嗜酸性粒细胞计数和白细胞介素-13（IL-13）分别存在因果联系（，）。EFEMP2也与嗜酸性粒细胞计数、IL-13和白细胞介素-17（IL-17）分别存在因果关系（，）。表型全基因组关联研究（PheWAS）分析显示CFL1与哮喘显著相关，而EFEMP2与哮喘和湿疹均相关。蛋白质-蛋白质相互作用（PPI）网络分析进一步揭示了EFEMP2和CFL1与免疫调节和炎症反应相关蛋白质的直接相互作用，网络中77.64%由直接结合组成，表明它们在调节AR相关免疫和炎症反应中的关键作用。值得注意的是，免疫相关途径与参与炎症反应的基因之间存在8.01%的显著相关性。