Investigating Mediating Factors in the Genetic Link Between Maternal Smoking Around Birth and Offspring's Cardiovascular Disease Risk

Introduction Maternal smoking around birth (MSAB) has been associated with adverse offspring health outcomes, but whether it causally increases offspring cardiovascular disease (CVD) risk remains unclear. We evaluated genetic associations of an MSAB proxy on offspring CVDs and explored potential mediating pathways. Methods We conducted a two-sample Mendelian randomization (MR) study using large genome-wide association study datasets predominantly of European ancestry. Genetic instruments for MSAB were obtained from offspring genotypes associated with reported maternal smoking around birth in the UK Biobank. Outcomes included atrial fibrillation (AF), heart failure (HF), coronary artery disease (CAD), and myocardial infarction (MI). Multivariable MR adjusted for offspring smoking initiation, and two-step MR mediation analyses assessed body mass index (BMI), type 2 diabetes mellitus (T2DM), and lipid traits as potential mediators. The inverse-variance weighted method was the primary analysis. Results Genetically predicted MSAB was associated with higher risks of AF (OR=2.23, 95% CI=1.28–3.92, p=4.93×10-3), HF (OR=3.84, 95% CI=1.91–7.76, p=1.70×10-4), and CAD (OR=4.50, 95% CI=1.16–17.51, p=0.03), but not MI. After adjustment for offspring smoking, the associations remained significant for HF (OR=3.88, 95% CI=1.57–9.55, p=3.22×10-3) and CAD (OR=6.23, 95% CI=2.23–17.40, p=4.82×10-4). Mediation analyses suggested that higher BMI and triglycerides, lower HDL-C and ApoA-I, and greater T2DM liability may partly mediate these associations. Conclusions Genetically proxied MSAB was associated with offspring CVD risk, particularly HF and CAD. Adiposity, dyslipidemia, and T2DM may represent important mediating pathways.