INTRODUCTION
Childhood obesity and asthma have posed a parallel epidemic over the
past three decades1. According to a meta-analysis of 6
prospective children studies, obesity was significantly associated with
2-fold times increased risk for incident asthma2.
Obese asthma is a complex syndrome, including different phenotypes of
diseases that warrant further investigations. Hence, identifying
obesity-related risk factors behind this causal relationship is
essential to inform preventive interventions. The obesity-related risk
factors could be composed of hereditary factors and lifestyle factors,
such as physical inactivity and inadequate sleep.
Multiple obesity-related factors may potentially contribute to the link
of childhood asthma; for example, physical activity or physical fitness
levels, poor sleep quality, and some obesity comorbidities, such as
sleep-disordered breathing (SDB), may also play a role. We previously
performed a bidirectional MR analysis, with the results suggesting that
adiposity antedates asthma3. Moreover, the causal
relationships between physical activity or physical fitness levels and
asthma have long been debated. Some studies have supported the causal
relationship between physical fitness and asthma incidence in
prospective studies4, 5, whereas others have reported
that physical fitness does not influence asthma
directly6. Moreover, poor sleep quality and SDB are
common in children with asthma. Prospective studies of insomnia and
new-onset asthma have been conducted in adults7, 8 but
not in children. Using two-sample MR analysis, Dashti et al. reported a
U-shaped association between sleep duration and asthma in an adult
study9. Although many studies have reported the
obesity-related factors leading to asthma, accurately appraising the
causality of these factors in asthma is essential for future preventive
interventions.
Epidemiological studies have identified some obesity-related factors
associated with asthma, but these associations can be subject to
confounding and reverse causations.
Mendelian randomization (MR) can
be used to strengthen causal inference indicated by observational
studies by using genetic variants as instrumental variables for risk
factors. A genetic risk score (GRS) for an individual obesity-related
factor can be regarded as a genetic proxy for this risk factor.
Therefore, if a certain obesity-related factor is causally related to
asthma, a GRS for this risk factor should also be associated with
asthma.
In this study, we addressed the aforementioned limitations of
traditional observational methods and focused on several obesity-related
factors (obesity, physical activity, cardiopulmonary physical fitness,
SDB, and sleep quality) in which candidate genetic instruments could be
defined. We aimed to (1) elucidate the causality of multiple
obesity-related factors and childhood asthma by using MR, (2) conduct
prospective analysis to strengthen the temporal relationship between
these risk factors and asthma, and (3) describe the inherited
susceptibility of each factor on asthma from representative GRSs.