欧洲人哮喘急性发作的全表观基因组关联研究

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans.

作者信息

Martin-Gonzalez Elena, Perez-Garcia Javier, Herrera-Luis Esther, Martin-Almeida Mario, Kebede-Merid Simon, Hernandez-Pacheco Natalia, Lorenzo-Diaz Fabian, González-Pérez Ruperto, Sardón Olaia, Hernández-Pérez José M, Poza-Guedes Paloma, Sánchez-Machín Inmaculada, Mederos-Luis Elena, Corcuera Paula, López-Fernández Leyre, Román-Bernal Berta, Toncheva Antoaneta A, Harner Susanne, Wolff Christine, Brandstetter Susanne, Abdel-Aziz Mahmoud Ibrahim, Hashimoto Simone, Vijverberg Susanne J H, Kraneveld Aletta D, Potočnik Uroš, Kabesch Michael, Maitland-van der Zee Anke H, Villar Jesús, Melén Erik, Pino-Yanes Maria

机构信息

Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain.

Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

出版信息

Allergy. 2025 Apr;80(4):1086-1099. doi: 10.1111/all.16490. Epub 2025 Feb 5.

DOI:10.1111/all.16490

PMID:39907155

Abstract

BACKGROUND

Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered.

OBJECTIVE

This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans.

METHODS

DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs (false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted.

RESULTS

Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality.

CONCLUSIONS

DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

摘要

背景

哮喘急性加重（AE）是全球哮喘负担的主要促成因素。尽管遗传和环境因素与AE有关，但表观遗传学的作用仍未明确。

目的

本研究旨在确定欧洲人中与AE相关的全血DNA甲基化（DNAm）标志物。

方法

使用Infinium MethylationEPIC微阵列（Illumina）对来自西班牙个体的406份血液样本进行DNAm评估。进行了一项全表观基因组关联研究，以测试DNAm与差异甲基化位置、区域和表观遗传模块处的AE之间的关联。对提示性地与AE相关的CpG（错误发现率[FDR]<0.1）在222名欧洲个体中进行重复验证，并在对发现和重复样本进行荟萃分析后宣布达到全基因组显著性（p<9×10）。使用来自155名西班牙个体的鼻组织DNAm数据进行了额外评估。通过顺式甲基化定量性状位点（meQTL）分析评估遗传变异对DNAm的影响。对先前全表观基因组关联研究（EWAS）信号进行了富集分析。

结果

四个CpG与AE相关，其中两个在荟萃分析中得到重复并达到基因组显著性（注释为ZBTB16和BAIAP2）。其中，CpG cg25345365（ZBTB16）在鼻上皮中进行了跨组织验证（p = 0.003），并与五个独立的meQTL相关（FDR<0.05）。此外，四个差异甲基化区域和一个模块与AE显著相关。富集分析显示，先前与产前和环境暴露、免疫介导疾病及死亡率的表观遗传关联存在过度富集。