Impact of fetal and maternal genetically predicted birth weight on cardiometabolic risk: a Mendelian randomization study of cytokine mediation in Europeans

Background Birth weight (BW) is influenced by both fetal and maternal genetic factors and is correlated with cardiometabolic outcomes later in life. Investigating these factors can clarify whether the association between BW and health risk arises from fetal, maternal, or shared genetic factors. Inflammation likely plays a key role in cardiometabolic risk related to BW. This study examined the causal effects of fetal and maternal genetically predicted BW on cardiometabolic outcomes, focusing specifically on the mediating role of inflammatory cytokines.Methods We used a two-sample Mendelian randomization (MR) framework to estimate the causal effects of fetal-specific and maternal-specific BW on ten cardiometabolic and autoimmune outcomes. Additionally, we conducted a two-step MR mediation analysis to assess the role of 41 core inflammatory cytokines in these effects. Exposure data for fetal-specific BW (n = 298,142) and maternal-specific BW (n = 210,267) were sourced from the EGG Consortium and UK Biobank. Outcome data were mainly obtained from GWAS consortia including FinnGen, Pan-UKBB, and DIAGRAM. Cytokine data were collected from Finnish cohorts. Genetic instruments (Single nucleotide polymorphisms, SNPs) were selected at p < 5 × 10−8, with F-statistics > 10 ensuring robustness. Primary analyses used inverse-variance weighted MR and conducted sensitivity analyses to evaluate pleiotropy.Results Fetal-specific BW was inversely associated with type 2 diabetes (T2D, OR = 0.585, 95% CI: 0.491–0.697), fasting glucose (FG, 0.918, 0.886–0.951), fasting insulin (FI, 0.907, 0.878–0.937), coronary artery disease (CAD, 0.782, 0.701–0.873), myocardial infarction (MI, 0.746, 0.650–0.855), and systemic lupus erythematosus (SLE, 0.432, 0.228–0.818), but positively associated with venous thromboembolism (VTE, 1.252, 1.108–1.416). Maternal-specific BW was inversely associated with FI (0.927, 0.889–0.966), hypertension (0.697, 0.564–0.861), CAD (0.775, 0.652–0.921), and MI (0.730, 0.593–0.897). Cytokines such as PDGF-BB, MIP-1β, SDF-1α, and IL-4 partially mediated the associations between fetal-specific BW, maternal-specific BW, and cardiometabolic outcomes, but their mediation proportions were limited.Conclusions This study provides evidence that both fetal and maternal genetically predicted BW independently influence cardiometabolic outcomes, with fetal genetic effects having a broader impact. Although inflammatory cytokines (PDGF-BB, MIP-1β, SDF-1α, IL-4) partially explain these effects, their contributions are limited, suggesting additional biological pathways underlie these lifelong associations.