Abstract：
OBJECTIVE: To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits.
METHODS: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHRadj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche.
RESULTS: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHRadj BMI). In female participants, increased birth weight causally decreased fasting insulin (betaIVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10-3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (betainverse-variance-weighted (IVW) , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10-4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex.
CONCLUSIONS: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course.
METHODS: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHRadj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche.
RESULTS: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHRadj BMI). In female participants, increased birth weight causally decreased fasting insulin (betaIVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10-3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (betainverse-variance-weighted (IVW) , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10-4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex.
CONCLUSIONS: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course.
摘要：
目的：评估肥胖相关人体测量特征对血糖性状的性别和时间特异性因果效应。
方法：我们使用单变量和多变量孟德尔随机化来评估人体测量特征的因果关联（妊娠变量，出生体重,儿童体重指数[BMI]，BMI,腰臀比[WHR]，BMI调整的WHR[WHRadjBMI]）与早期生长遗传学联盟的欧洲人的空腹血糖和胰岛素（n≤298142），英国生物银行,人体测量性状联合会的遗传调查（n≤697734；女性：n≤434794；男性：n≤374754）以及葡萄糖和胰岛素相关性状联合会的荟萃分析（n≤151188；女性：n≤73089；男性：n≤67506），调整母体的遗传效应，吸烟,酒精消费,和初潮的年龄。
结果：我们观察到妊娠变量的关联为零，出生体重的负关联，以及儿童期BMI和成人特征的正相关(BMI，WHR,和WHRadjBMI）。在女性参与者中，出生体重增加导致空腹胰岛素减少(betaIVW，-0.07，95%置信区间[CI]-0.11至-0.03；p=1.92×10-3)，但不是葡萄糖水平，通过调整初潮年龄而废除了。在男性参与者中，出生体重增加导致空腹血糖下降(甜菜碱方差加权(IVW)，-0.07，95%CI-0.11至-0.03；p=3.22×10-4)，但不是胰岛素水平.在特定时间的分析中，女性参与者不存在出生体重的独立影响，在男性参与者中更为明显。男女儿童BMI的独立影响均减弱；成人特征的独立影响因性别而异。
结论：我们的发现为性别和时间特异性人体测量特征对血糖变量的因果和独立影响提供了证据。并强调了在生命过程中不同时间点考虑多种肥胖暴露的重要性。
方法：我们使用单变量和多变量孟德尔随机化来评估人体测量特征的因果关联（妊娠变量，出生体重,儿童体重指数[BMI]，BMI,腰臀比[WHR]，BMI调整的WHR[WHRadjBMI]）与早期生长遗传学联盟的欧洲人的空腹血糖和胰岛素（n≤298142），英国生物银行,人体测量性状联合会的遗传调查（n≤697734；女性：n≤434794；男性：n≤374754）以及葡萄糖和胰岛素相关性状联合会的荟萃分析（n≤151188；女性：n≤73089；男性：n≤67506），调整母体的遗传效应，吸烟,酒精消费,和初潮的年龄。
结果：我们观察到妊娠变量的关联为零，出生体重的负关联，以及儿童期BMI和成人特征的正相关(BMI，WHR,和WHRadjBMI）。在女性参与者中，出生体重增加导致空腹胰岛素减少(betaIVW，-0.07，95%置信区间[CI]-0.11至-0.03；p=1.92×10-3)，但不是葡萄糖水平，通过调整初潮年龄而废除了。在男性参与者中，出生体重增加导致空腹血糖下降(甜菜碱方差加权(IVW)，-0.07，95%CI-0.11至-0.03；p=3.22×10-4)，但不是胰岛素水平.在特定时间的分析中，女性参与者不存在出生体重的独立影响，在男性参与者中更为明显。男女儿童BMI的独立影响均减弱；成人特征的独立影响因性别而异。
结论：我们的发现为性别和时间特异性人体测量特征对血糖变量的因果和独立影响提供了证据。并强调了在生命过程中不同时间点考虑多种肥胖暴露的重要性。
