Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study

Abstract

Background: Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus (GDM), the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified.

Aim: To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM.

Methods: Mendelian randomization (MR) was conducted using data from genome-wide association studies of European populations. We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments, and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM. In addition, we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors.

Results: A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM (OR: 0.71, 95%CI: 0.60-0.84). Among the metabolic factors assessed, four emerged as potential mediators of the education-GDM association, which, ranked by mediated proportions, were as follows: Waist-to-hip-ratio (31.56%, 95%CI: 12.38%-50.70%), body mass index (19.20%, 95%CI: 12.03%-26.42%), high-density lipoprotein cholesterol (12.81%, 95%CI: 8.65%-17.05%), and apolipoprotein A-1 (7.70%, 95%CI: 4.32%-11.05%). These findings proved to be robust to sensitivity analyses.

Conclusion: Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.

Keywords: Educational status; Gestational diabetes mellitus; Lifestyle factors; Mendelian randomization analysis; Metabolism.

Figure 1

Mendelian randomization estimates of proportional mediation by candidate mediators in the causal relationship between educational attainment and gestational diabetes mellitus. HDL-C: High-density lipoprotein cholesterol; BMI: Body mass index; WHR: Waist-to-hip ratio.