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

Abstract

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. Method Genetic variants form GWAS summary-level data of own BW (N = 298,142), offspring BW (N = 210,267 mothers) and 16 cardiometabolic factors (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. Then, mediation analyses were conducted to analyze the potential mediating effects of 16 cardiometabolic factors using two-step MR. Result Inverse variance weighted method exhibited lower BW raised the CHD risk (β: -0.30; 95%CI: -0.40, -0.20) and consistent results were observed in fetal/maternal-specific BW. We identified 5 mediators in the causal pathway from BW to CHD, including hip circumference adjust body mass index, triglycerides, diastolic blood pressure, systolic blood pressure (SBP), with mediated proportion ranging from 7.44% for triglycerides to 27.75% for SBP. Causality between fetal/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 the fetal/maternal specific BW may both contribute to this effect. The causality between BW and CHD was mediated by several cardiometabolic factors.

Mendelian randomization shows causal effects of birth weight and childhood body mass index on the risk of frailty

“…A lower birth weight has been linked to impaired neuroendocrine and immune systems, contributing to the development of frailty in old age (26). Furthermore, based on the understanding that birth weight is influenced by both the development of the fetus and the intrauterine environment, we categorized birth weight factors into fetal and maternal effects as previously described (12,14,16,27). The MR findings indicate that the fetal effect on birth weight has a stronger influence on the risk of frailty than the maternal effect, suggesting that the birth weight-frailty association may be more attributable to the fetal effects than to the maternal effects (intrauterine environment) (16).…”

“…Since birth weight is affected by both infant development (infants) and the intrauterine environment (mothers), it is important to distinguish the role of fetal effect and maternal effect on birth weight (12). Based on the studies published previously (7,(12)(13)(14)(15)(16), the birth weight components could be divided into the maternal effect and the fetal effect (16). The data on own birth weight, offspring birth weight (maternal-specific), and childhood BMI were summarized from the Early Growth Genetics (EGG) Consortium, which included 298,142, 210,267, and 39,620 participants respectively, of European descent (17,18).…”