Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Nat Commun. 2024 May 28;15(1):4546. doi: 10.1038/s41467-024-48507-7.
Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10 and CPA3; p = 2.39 × 10) and wound healing (FN1; p = 7.63 × 10). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora.
哮喘在不同祖先群体中存在显著差异，但这些差异的分子基础理解甚少，研究也很少。美洲非洲裔人群哮喘联盟（CAAPA）的目标之一是了解以非洲裔人群为重点的哮喘多组学特征。从鼻腔上皮组织中获取了 RNA-seq 和 DNA 甲基化数据，包括来自 7 个不同地理区域的 253 例哮喘病例（当前哮喘）和 283 例对照（从未患过哮喘），以识别差异表达基因（DEGs）和基因网络。我们确定了 389 个 DEGs；排名最高的 DEG，FN1，在病例中下调（q = 3.26×10），编码纤连蛋白，在伤口愈合中发挥作用。排名前三的基因表达模块提示与免疫反应（CEACAM5；p = 9.62×10 和 CPA3；p = 2.39×10）和伤口愈合（FN1；p = 7.63×10）相关的网络。多组学分析鉴定出 FKBP5，它是糖皮质激素受体信号的共伴侣，已知与哮喘中的药物反应有关，鼻上皮基因表达的关联可能受甲基化调控，并与吸入性皮质类固醇的使用增加有关。这项工作揭示了三个轴上的分子失调 - 增加的 Th2 炎症、伤口愈合能力下降和药物反应受损 - 这可能在非洲侨民的哮喘中发挥关键作用。
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