Genetic evidence for the effect of prepregnancy maternal metabolic status on the risk of congenital heart disease in offspring: A Mendelian randomization study

Congenital heart disease (CHD) is the most common birth defect in the world and is still one of the most common causes of illness and death in babies. There are links between maternal metabolic factors, like glycemic and lipid profiles, and the disease, but it is not clear if these links are causal. Using a two-sample Mendelian randomization (MR) method, this study looked at whether maternal HbA1c, fasting glucose, and triglyceride levels could cause an increase in the risk of CHD in offspring. We selected independent genome-wide significant single-nucleotide polymorphisms (SNPs) (P < 5 × 10-8) representing maternal pregestational metabolic traits and harmonized them with summary-level genome-wide association study (GWAS) data for CHD (16,743 cases; 280,081 controls) from FinnGen Release 9 and Biobank Japan. We applied inverse-variance weighted (IVW), MR-Egger regression, and weighted median methods to perform both univariable and multivariable MR analyses. Higher genetically predicted levels of HbA1c and triglycerides were strongly linked to a higher risk of CHD (HbA1c IVW β = 0.218, P = .0001; triglycerides IVW β = 0.305, P = 1.2 × 10-6). The link for fasting glucose was weaker and less stable. Sensitivity analyses showed horizontal pleiotropy but not much heterogeneity. In multivariable MR models, the links between HbA1c and triglycerides stayed strong. Our findings provide genetic evidence that maternal pregestational glycemic and lipid metabolic status may causally contribute to the risk of CHD in offspring. These results emphasize the importance of optimizing maternal metabolic health before conception and highlight the need for further research to clarify underlying mechanisms and evaluate potential preventive strategies.