Elucidating the causal role of age of menarche, adiposity, lipid fractions, and blood pressure upon cardiovascular disease: a multivariable Mendelian randomization study

This study explores the causal role of multiple correlated risk factors in coronary heart disease (CHD) and ischemic stroke, using Mendelian randomization (MR) analyses with GWAS summary data from both prevalent and incident stroke cases. Thirteen candidate risk factors were considered, including age at menarche, adiposity, lipid fractions, blood pressure, and smoking. Univariable MR identified seven exposures significantly associated with CHD risk, including BMI, blood pressure, LDL, triglycerides, type-II diabetes, and smoking. Notably, HDL showed a protective effect (OR = 0.77, 95% CI: 0.72–0.83), while type-II diabetes was positively associated with CHD (OR = 1.10, 95% CI: 1.05–1.16). For ischemic stroke subtypes, diastolic and systolic blood pressure showed consistent effects across both small vessel and large artery stroke (e.g., DBP OR = 2.27, 95% CI: 1.77–2.89 for small vessel stroke), and HDL again demonstrated protective effects. Multivariable MR (MVMR) further confirmed these associations, though estimates were attenuated. In summary, both univariable and MVMR analyses identified robust associations of lipid fractions and blood pressure with cardiovascular outcomes, highlighting their importance in CHD and ischemic stroke risk across multiple stroke subtypes.