INTRODUCTION
Obesity and asthma are common in children, and obesity has been
identified as a significant risk factor for asthma in several
longitudinal1 and Mendelian randomization (MR)2 studies, but the mechanism underlying their
association remains unknown. Genetic factors, environmental
exposures,3 mechanical effects (e.g.,
obesity-associated lung function decline), inflammation (as measured by
fractional exhaled nitric oxide (FeNO)), lifestyle
(e.g., physical activity and diet), common comorbidities, and endocrine
factors (e.g., adipokines and reproductive hormone) have all been
implicated.4 However, the relationship between obesity
and airway inflammation is inconsistent;5 and although
obesity-related physical activity levels and poor physical fitness have
been found to trigger the onset of asthma,6-8 few
studies have evaluated whether physical fitness mediates an increased
risk of obesity-induced asthma. Similarly, comorbidities of obesity such
as dyslipidemia, gastroesophageal reflux, and sleep-disordered breathing
(SDB), are known to provoke asthma;4 both SDB and
asthma involve airway obstruction and share “obesity” as their
significant risk factor,9 and treatment of SDB can
mitigate asthmatic symptoms.10 However, a possible
mediating role of SDB in the relationship between obesity and asthma has
yet to be unexplored. Finally, though endocrine factors (which are
expressed as early puberty in the current study) can be a crucial
mediating pathway from obesity to asthma,11 and a
causal relationship between early puberty and asthma has been
suggested,11,12 but no estimates of mediation
proportion from obesity and early puberty to asthma have been reported.
Several pathways might explain the pathophysiology underlying the
association between obesity and asthma. However, past evidence is mostly
limited to observational studies, whose analyses are limited by
confounding factors and reverse causation. MR
studies13 use genetic variants that can divide the
observed population into different subgroups according to the exposure
level; therefore, it is analogous to a randomized controlled trial
(RCT). Network MR studies use genetic variants as instrumental variables
(IVs) to investigate mediation in causal pathways.14When genetic IVs are obtained for obesity and mediators in the
obesity–asthma link, the direct and indirect effects of obesity on
asthma can be estimated through network MR. If a mediation pathway is
crucial, then an intervention focusing on reducing mediators may be as
effective as weight reduction intervention in reducing asthma risk.
To improve our understanding of mechanisms and pathways that underlie
obese asthma, we undertook a network MR analysis of data from the Taiwan
Children Health Study (TCHS) to study and quantify the influence of five
possible mediators of obesity-induced asthma: (1) pulmonary function
impairment, (2) airway inflammation, (3) low physical fitness, (4) SDB,
and (5) early puberty. Then, significant mediators identified from MR
analysis will be confirmed in prospective cohort analyses. Our results
enable the importance of each mediator to be compared, which will inform
the prioritization of future interventional studies targeting the
mediating pathway of obese children, to prevent asthma.