DISCUSSION
Our study has yielded new evidence for several potential mechanistic factors underlying the causative relationship between obesity and asthma. We used the network MR to examine causal mediation pathways and to confirm the temporal causality using prospective cohort analyses. Among the five mediators examined in the current study, impaired pulmonary function, low physical fitness, and early puberty were found to be robust mediators, whereas SDB was identified as a possible mediator. However, airway inflammation did not appear to be a causal mediator. Low FEV1/FVC and physical fitness were the top two leading mediation pathways. A recent interventional study wherein obese asthmatic patients were provided high-intensity pulmonary rehabilitation programs did lead to experience significant improvements in asthma control.34 Hence, the promotion of physical fitness to improve pulmonary functions should be recommended for obese children, to prevent asthma.
According to this network MR study, obesity-induced low physical fitness and impaired pulmonary function are the main mediation pathways presenting 91.42% and 61.57% of the mediation proportion, respectively (Figure 4). Determining the causal links between physical fitness and asthma incidence is crucial in guiding clinical practice. However, there is limited proof for the causal relationship between physical fitness and the incidence of asthma. In a Danish study of school-aged children, Rasmussen et al. reported an association between poor physical fitness in childhood and incidence of asthma in young adulthood.6 The authors then combined this result with a New Zealand-based study, and concluded that improving fitness during childhood was associated with a higher lung volume in adulthood.8 Additionally, Ortega et al. discovered that among obese individuals, high cardiorespiratory fitness could reduce the risk of asthma by half.35 Examining the temporal sequence of low physical fitness and asthma development in a longitudinal study is time-consuming and laborious, and testing this hypothesis in a controlled trial is not feasible. To our knowledge, this is the first MR study to investigate the causal relationship between physical fitness and asthma. Additionally, the indirect effects mediated through low physical fitness and impaired pulmonary function are much higher than the direct effects, indicating that enhancing physical fitness and pulmonary function could effectively prevent obesity-induced asthma.
Childhood obesity is a major contributor of both early puberty and asthma. In the current study, we identified a moderate degree of mediation (mediation proportion, 28.28%) for early puberty in the pathogenesis from obesity to asthma. We previously confirmed the causality between early puberty and asthma for both sexes through MR and longitudinal studies.11 Boys and girls showed a 1.38- and 1.11-fold increased risk of asthma, respectively, with early puberty.11 Underlying causes linking early puberty and asthma could be hormonal changes at puberty,36decreased pulmonary function in those with early puberty,37 and hyperinsulinemia during the pubertal growth stage.38 One case report stated that pharmacological therapy (such as a gonadotropin-releasing hormone analog) could be administered to prevent asthma in children experiencing early puberty.39 To prevent obesity-induced asthma risk, clinicians must assess for the presence of early puberty.
Our study, which used a MR network analysis, adds to the existing evidence suggesting bi-directional relationships between SDB and asthma. We confirmed the causality from SDB to asthma. Moreover, we observed that SDB is a potential mediator with a moderate mediation proportion in the pathogenesis of obesity-induced asthma. Although causal relationships between SDB and asthma were never determined using a cohort study,40 treatment of SDB, such as adenotonsillectomy, showed improved asthma outcomes.41Possible mechanisms linking SDB and asthma include airway edema or obstruction and systemic inflammation.34 SDB-related hypoxia can induce reflex bronchoconstriction, which further causes asthma.42 Additional RCTs are needed to confirm that the treatment of SDB improves pediatric asthma outcomes.
Our study has three key strengths. First, it is the large population-based study on children that involved various mediator measurements linking obesity and asthma. Second, we applied three distinct statistical analyses (observational, MR, and prospective cohort analyses) to prove the robustness of interrelations among obesity, the mediators (impaired pulmonary function, low physical fitness, and early puberty), and asthma. Moreover, several sensitivity analyses for MR results were performed to support our findings. The present study also has several limitations that should be addressed. First, SDB was defined using a questionnaire-based assessment instead of measuring it through polysomnography (PSG). This approach is common in the SDB/asthma literature,43 where the cost involved in technology and personnel make such a large population-based study cost-prohibitive. However, the CSHQ is a well-established instrument for SDB assessment, with good performance in population-based studies as compared with the gold standard PSG.21 Second, a lack of the association of elevated FeNO with both obesity and asthma in the MR analysis could be due to weak genetic instruments. In contrast to the genome-wide association study approach, the candidate SNP approach was limited by only a few available literatures on genetic variants relevant to FeNO.44
In summary, impaired pulmonary function, low physical fitness, and early puberty are prominent mediating mechanisms for obesity-induced asthma. Therefore, lifestyle interventions aimed at promoting physical fitness and pulmonary function might effectively reduce the risk of obese asthma. Assessing these promising mediators may deepen our understanding of its pathogenic features and may offer new treatment strategies for specific phenotypes of obese asthma.