中国麻风皮肤病杂志 ›› 2025, Vol. 41 ›› Issue (12): 869-875.doi: 10.12144/zgmfskin202512869

• 论著 • 上一篇    下一篇

基于全基因关联分析和蛋白质组学共定位分析鉴定特应性皮炎治疗新靶点

孙亚如1,2,张翼升3,陈瑶2,陈金波2,陈柳青2   

  1. 1湖北中医药大学中医学院，湖北武汉，430065;2湖北中医药大学附属中西医结合医院皮肤科，湖北武汉，430022;3广西中医药大学第一附属医院脊柱骨伤科，广西南宁，530000
  • 出版日期:2025-12-15 发布日期:2025-11-27

Identification of novel therapeutic targets for atopic dermatitis based on genome-wide associationstudies and proteomic colocalization analysis

SUN Yaru1,2, ZHANG Yisheng3, CHEN Yao2, CHEN Jinbo2, CHEN Liuqing2   

  1. 1 College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China; 2 Department of Dermatology, Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan 430022, China; 3 Department of Spinal Orthopedics, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530000, China
  • Online:2025-12-15 Published:2025-11-27

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摘要： 目的：研究特应性皮炎（atopic dermatitis,AD）新的治疗靶点。方法：利用英国生物样本库制药蛋白组学项目的2923种蛋白质的蛋白质数量性状位点数据和芬兰数据库中AD的GWAS数据，进行孟德尔随机化分析、共定位分析和全表型组关联研究分析。结果：双样本孟德尔随机化结果显示HSPB6、LAT、LDLRAP1、FGR、CSF2、INPP5D、MDM1、FKBP1B、MMP12和IL7R蛋白质表达可能增加AD患病风险，IL36A、SF3B4、SEPTIN8、APOA1、BOLA1、SV2A和B4GAT1蛋白质表达可降低AD患病风险。对TSMR进行敏感性分析，SMR分析显示SV2A、APOA1、SF3B4、BOLA1、INPP5D、MMP12、FGR、HSPB6、LAT、FKBP1B和IL36A血浆蛋白表达水平与AD之间的关联不是由连锁不平衡引起的。然后通过贝叶斯共定位分析发现INPP5D、MMP12、LAT及IL36A与AD共享相同的因果变异，最后利用全表型组关联研究证明以上4个潜在药物靶标与基因水平的其他性状之间并未表现出显著相关性。结论：INPP5D、MMP12、LAT及IL36A蛋白与AD的发病率具有相关性，作用于靶标的药物不良反应较小，可为开发新的治疗策略提供理论依据。

关键词: 特应性皮炎, 孟德尔随机化, 共定位分析, 全蛋白组学, 全基因组关联研究

Abstract: Objective: To investigate novel therapeutic targets for atopic dermatitis (AD). Methods: Mendelian randomization analysis, colocalization analysis, and phenome-wide association study (PheWAS) were conducted using protein quantitative trait locus (pQTL) data of 2,923 proteins from the UK Biobank Pharma Proteomics Project and genome-wide association study (GWAS) data of AD from Finnish databases. Results: Two-sample Mendelian randomization results showed that the expression levels of proteins including HSPB6, LAT, LDLRAP1, FGR, CSF2, INPP5D, MDM1, FKBP1B, MMP12, and IL7R may increase the risk of AD, while the expression levels of IL36A, SF3B4, SEPTIN8, APOA1, BOLA1, SV2A, and B4GAT1 may reduce the risk of AD. Sensitivity analysis was performed for transcriptome-wide Mendelian randomization (TSMR), and summary data-based Mendelian randomization (SMR) analysis indicated that the associations between the plasma expression levels of SV2A, APOA1, SF3B4, BOLA1, INPP5D, MMP12, FGR, HSPB6, LAT, FKBP1B, IL36A and AD were associated with AD independently. Subsequently, Bayesian colocalization analysis revealed that INPP5D, MMP12, LAT, and IL36A shared the same causal variants with AD. Finally, PheWAS demonstrated that these four potential drug targets did not show significant correlations with other traits at the genetic level. Conclusion: INPP5D, MMP12, LAT, and IL36A proteins are associated with the incidence of AD. Drugs targeting these proteins may have fewer adverse reactions, and this study provides a theoretical basis for the development of new therapeutic strategies for AD.

Key words: atopic dermatitis, Mendelian randomization, colocalization analysis, proteome-wide, genome-wide association study