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.