Sex- and time-specific associations of obesity with glycaemic traits: A two-step multivariate Mendelian randomization study.

Abstract

AIM:

To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits.

MATERIALS AND 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.

• Authors: Ye Tian, Guochen Ma, Jing Zi, Yifan Hu, Yaxian Zeng, Haoqi Li, Hang Luo, Shufang Shan, Jingyuan Xiong, Guo Cheng
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 26 Issue 4 Pg. 1443-1453 (Apr 2024) ISSN: 1463-1326 [Electronic] England
• PMID: 38240050 (Publication Type: Journal Article)
• Copyright: © 2024 John Wiley & Sons Ltd.

Chemical References

• Insulin
• Glucose

Topics

• Adult
• Humans
• Male
• Female
• Birth Weight (genetics)
• Mendelian Randomization Analysis
• Obesity (epidemiology, genetics, complications)
• Body Mass Index
• Insulin (genetics)
• Glucose
• Genome-Wide Association Study
• Polymorphism, Single Nucleotide