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.