与严重哮喘发作相关的21号染色体变异：巴西人群的全基因组关联研究
Chromosome 21 variants tied to severe asthma exacerbations: A genome-wide association study in a Brazilian population.
作者信息
de Santana Maria B R, Cruz Álvaro A, Teixeira Helena M P, Silva Hatilla Dos S, Abdel-Aziz Mahmoud I, Hashimoto Simone, Vijverberg Susanne J H, Herrera-Luis Esther, Pino-Yanes Maria, Burchard Esteban G, Chung Kian Fan, Djukanovic Ratko, Dahlén Sven-Erik, Adcock Ian M, Cox Corey, Brunetti Tonya, Campbell Monica, Rafaels Nicholas, Barnes Kathleen C, Maitland-van der Zee Anke H, Figueiredo Camila A, Costa Ryan S
机构信息
Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
Fundação PROAR and Universidade Federal da Bahia, Salvador, Bahia, Brazil.
出版信息
J Allergy Clin Immunol Glob. 2025 Jun 2;4(3):100507. doi: 10.1016/j.jacig.2025.100507. eCollection 2025 Aug.
BACKGROUND
Asthma exacerbations are episodes of symptom worsening requiring increased therapy, which affect patients across all asthma severities. Potential genetic associations with asthma exacerbations in an understudied population were investigated.
OBJECTIVE
We sought to perform a genome-wide association study on severe asthma exacerbations in an admixed adult population with varying asthma severities and to explore potential epigenetic roles.
METHODS
A genome-wide association study was conducted in 727 Brazilian patients (mean age, 43 years; 20% male; and 55% with exacerbations) from the Programa de Controle da Asma na Bahia study, analyzing 12 million variants. Severe exacerbation was defined as systemic corticosteroid use for 3 or more days, emergency room visits, or hospital admissions within the past year. Analyses were adjusted for age, sex, asthma severity, and genotype principal components. Replication was sought in the cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (UBIOPRED) study, the Genes-environments and Admixture in Latino Americans II study, and the Study of African Americans, Asthma, Genes, and Environments using the same methodology. Epigenetic effects were assessed via PhenoScanner v2.
RESULTS
Five intergenic variants (rs55670125, rs10854420, rs68160941, rs11910414, and rs35834033) in complete linkage disequilibrium reached genome-wide significance (odds ratio [OR], 2.5; = 3.47 × 10), located between the and genes on chromosome 21. Although not replicated, rs35834033 showed a nonsignificant trend (OR, 1.79; = .17). Four variants were associated with H3K4me1 histone modification, linked to asthma pathogenesis. In addition, 88 suggestive variants were found; rs17697822 in was negatively associated with exacerbations (OR, 0.44; = 4.03 × 10).
CONCLUSIONS
The CXADR is highlighted as a potential novel susceptibility locus for asthma exacerbations, possibly tied to viral respiratory infections. Further replication and validation are needed.
背景
哮喘急性加重是症状恶化且需要增加治疗的发作，影响所有哮喘严重程度的患者。在一个研究较少的人群中调查了与哮喘急性加重潜在的基因关联。
目的
我们试图在一个具有不同哮喘严重程度的混合成年人群中对严重哮喘急性加重进行全基因组关联研究，并探索潜在的表观遗传作用。
方法
在来自巴伊亚州哮喘控制项目研究的727名巴西患者（平均年龄43岁；20%为男性；55%有急性加重）中进行全基因组关联研究，分析1200万个变异。严重急性加重定义为在过去一年中使用全身性皮质类固醇3天或更长时间、急诊就诊或住院。分析针对年龄、性别、哮喘严重程度和基因型主成分进行了调整。在预测呼吸道疾病结局无偏倚生物标志物（UBIOPRED）研究、拉丁裔美国人基因 - 环境与混合研究II以及非裔美国人哮喘、基因与环境研究的队列中使用相同方法进行重复验证。通过PhenoScanner v2评估表观遗传效应。
结果
处于完全连锁不平衡状态的5个基因间变异（rs55670125、rs10854420、rs681,60941、rs11910414和rs35834033）达到全基因组显著性（比值比[OR]，2.5； = 3.47 × 10），位于21号染色体上的 和 基因之间。虽然未得到重复验证，但rs35834033显示出无统计学意义的趋势（OR，1.79； = 0.17）。4个变异与H3K4me1组蛋白修饰相关，与哮喘发病机制有关。此外，发现了88个提示性变异； 中的rs17697822与急性加重呈负相关（OR，0.44； = 4.03 × 10）。
结论
CXADR被突出显示为哮喘急性加重潜在的新易感基因座，可能与病毒性呼吸道感染有关。需要进一步的重复验证。
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