Probst-Hensch Nicole, Jeong Ayoung, Stolz Daiana, Pons Marco, Soccal Paola M, Bettschart Robert, Jarvis Deborah, Holloway John W, Kronenberg Florian, Imboden Medea, Schindler Christian, Lovison Gianfranco F
Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
Department of Public Health, University of Basel, Basel, Switzerland.
Front Public Health. 2021 May 11;9:584955. doi: 10.3389/fpubh.2021.584955. eCollection 2021.
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 (FEV) 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; = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; = 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.
肥胖与呼吸健康有着复杂的联系。孟德尔随机化(MR)能够评估体重指数(BMI)对气流阻塞和呼气中期流量影响的因果关系。在成人SAPALDIA队列研究中,基线时招募了9651名年龄在18 - 60岁的具有人群代表性的样本(女性占51%),在20年的随访期间对BMI、第1秒用力呼气容积(FEV)与用力肺活量(FVC)的比值以及用力呼气中期流量(FEF25 - 75%)进行了三次测量。通过使用加权BMI等位基因评分作为工具变量和两阶段最小二乘法(2SLS)的孟德尔随机化分析,在预测模型(第1次和第2次随访期间的BMI平均值,第2次和第3次随访期间的肺功能(LF)平均值;n = 2850)和长期横断面模型(所有随访期间的BMI和LF平均值;n = 2728)中评估儿童期和成年期BMI对FEV1/FVC和FEF25 - 75%的因果效应。应用了三种不同的BMI等位基因评分,以专门捕捉成年期BMI中可能反映儿童期遗传决定的BMI轨迹的部分。主要因果效应来自包含BMI(由BMI遗传评分作为工具变量)、年龄、性别、身高和吸烟包年数作为协变量的模型。BMI相互作用由工具变量(BMI遗传评分)与相关伴随变量的乘积作为工具变量。在预测模型和长期横断面模型中均观察到BMI对FEV1/FVC和FEF25 - 75%的因果效应。BMI与LF的因果效应为负,且随年龄增长而减弱,如果由与儿童期BMI相关的基因评分作为工具变量则更强。这种探究乘法相互作用因果效应的非标准MR方法表明,儿童期BMI模式中基于遗传的部分可能与生命后期的小气道功能水平和气流阻塞特别相关。这些结果在方法学上的意义首先在于指出了生命历程视角在研究BMI对呼吸健康病因学作用中的重要性,其次在于指出了未来关于肥胖相关表型因果效应的MR研究中需要考虑的新方法学方面。