Birth Weight, Cardiometabolic Factors, and Coronary Heart Disease: A Mendelian Randomization Study.

Context: Observational studies have shown associations of birth weight (BW) with coronary heart disease (CHD), but results are inconsistent and do not distinguish the fetal or maternal effect of BW.

Objective: This study aims to explore the causal association between BW and CHD, analyze the fetal and maternal contribution, and quantify mediating effects of cardiometabolic factors.

Methods: Genetic variants from genome-wide association study summary-level data of own BW (N = 298 142), offspring BW (N = 210 267 mothers), and 16 cardiometabolic (anthropometric, glycemic, lipidemic, and blood pressure) factors were extracted as instrumental variables. We used two-sample Mendelian randomization study (MR) to estimate the causal effect of BW on CHD (60 801 cases and 123 504 controls from mixed ancestry) and explore the fetal and maternal contributions. Mediation analyses were conducted to analyze the potential mediating effects of 16 cardiometabolic factors using two-step MR.

Results: Inverse variance weighted analysis showed that lower BW raised the CHD risk (β -.30; 95% CI: -0.40, -0.20) and consistent results were observed in fetal-specific/maternal-specific BW. We identified 5 mediators in the causal pathway from BW to CHD, including body mass index-adjusted hip circumference, triglycerides, fasting insulin, diastolic blood pressure, and systolic blood pressure (SBP), with mediated proportion ranging from 7.44% for triglycerides to 27.75% for SBP. Causality between fetal-specific and maternal-specific BW and CHD was mediated by glycemic factors and SBP, respectively.

Conclusion: Our findings supported that lower BW increased CHD risk and revealed that fetal-specific and maternal-specific BW may both contribute to this effect. The causality between BW and CHD was mediated by several cardiometabolic factors.