Abstract
Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.
Highlights
Obesity, mostly measured as body mass index (BMI) is an established asthma risk factor
We evaluated causal effects (a) of BMI averaged over time points 1 and 2 on lung function averaged over time points 2 and 3 and (b) of BMI and lung function averaged over 3 time points
Analysis Scheme We investigated the causal association in a predictive model and in a long-term cross-sectional model (BMI and lung function (LF) both averaged over SAP1, SAP2, and SAP3; referred to as SAP1-SAP2-SAP3)
Summary
Mostly measured as body mass index (BMI) is an established asthma risk factor. Its etiological role with regard to other respiratory phenotypes including chronic obstructive pulmonary disease (COPD) remains unclear [1,2,3,4]. Observational evidence on the association of obesity with spirometry-derived lung function (LF) is inconclusive [5,6,7,8,9,10,11,12]. In adulthood, increasing BMI has been often, but not exclusively, associated with lower forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). FEV1/FVC was sometimes preserved or even increased in the presence of excess body weight, but overall the association with airflow obstruction (AO) remains unclear [12]. Inconsistencies between studies reflect differences in the study populations (age, health state, ethnicity, lifestyles, environments, socio-economic profile), differences in obesity parameters studied, and statistical models (confounders and effect modifiers considered)
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