Zaied Roan E, Gokuladhas Sreemol, Walker Caroline, O'Sullivan Justin M
The Liggins Institute, The University of Auckland, Auckland, New Zealand.
Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Front Immunol. 2024 Nov 19;15:1412032. doi: 10.3389/fimmu.2024.1412032. eCollection 2024.
Asthma is a heterogeneous condition that is characterized by reversible airway obstruction. Childhood-onset asthma (COA) and adult-onset asthma (AOA) are two prominent asthma subtypes, each with unique etiological factors and prognosis, which suggests the existence of both shared and distinct risk factors.
Here, we employed a two-sample Mendelian randomization analysis to elucidate the causal association between genes within lung and whole-blood-specific gene regulatory networks (GRNs) and the development of unspecified asthma, COA, and AOA using the Wald ratio method. Lung and whole blood-specific GRNs, encompassing spatial eQTLs (instrumental variables) and their target genes (exposures), were utilized as exposure data. Genome-wide association studies for unspecified asthma, COA, and AOA were used as outcome data in this investigation.
We identified 101 genes that were causally linked to unspecified asthma, 39 genes causally associated with COA, and ten genes causally associated with AOA. Among the identified genes, 29 were shared across some, or all of the asthma subtypes. Of the identified causal genes, had the strongest causal association with both unspecified asthma (OR: 1.49; 95% CI:1.42-1.57; p=7.30x10) and COA (OR: 3.37; 95% CI: 3.02-3.76; p=1.95x10), whereas had the strongest causal association with AOA (OR: 1.28; 95% CI: 1.16-1.41; p=0.007).
This study identified shared and unique genetic factors causally associated with different asthma subtypes. In so doing, our study emphasizes the need to move beyond perceiving asthma as a singular condition to enable the development of therapeutic interventions that target sub-type specific causal genes.
哮喘是一种异质性疾病，其特征为可逆性气道阻塞。儿童期起病哮喘（COA）和成人期起病哮喘（AOA）是两种主要的哮喘亚型，各有独特的病因和预后，这表明存在共同和不同的危险因素。
在此，我们采用两样本孟德尔随机化分析，使用Wald比率法阐明肺和全血特异性基因调控网络（GRNs）中的基因与未特定类型哮喘、COA和AOA发生之间的因果关联。将包含空间eQTLs（工具变量）及其靶基因（暴露因素）的肺和全血特异性GRNs用作暴露数据。在本研究中，将未特定类型哮喘、COA和AOA的全基因组关联研究用作结局数据。
我们鉴定出101个与未特定类型哮喘有因果关联的基因、39个与COA有因果关联的基因以及10个与AOA有因果关联的基因。在鉴定出的基因中，29个在部分或所有哮喘亚型中是共有的。在鉴定出的因果基因中， 与未特定类型哮喘（比值比：1.49；95%置信区间：1.42 - 1.57；p = 7.30×10）和COA（比值比：3.37；95%置信区间：3.02 - 3.76；p = 1.95×10）均有最强的因果关联，而 与AOA有最强的因果关联（比值比：1.28；95%置信区间：1.16 - 1.41；p = 0.007）。
本研究鉴定出了与不同哮喘亚型有因果关联的共同和独特遗传因素。通过这样做，我们的研究强调了有必要超越将哮喘视为单一疾病的认知，以便开发针对亚型特异性因果基因的治疗干预措施。
