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.