Genetically Predicted Levels of Lipoprotein(a) and Risk of Cerebrovascular Disease

Background Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. Methods We obtained genetic associations with Lp(a) levels ( n =343 681), ischemic stroke subtypes (≤62 100 cases), intracranial hemorrhage subtypes (≤15 400 cases), and 12 related cerebrovascular phenotypes. Lp(a) was proxied using 2 LPA genetic variants (rs10455872 and rs3798220) that explain 36% of the variance in Lp(a) levels. We performed Mendelian randomization analyses to estimate the association of a genetically predicted 100 nmol/L increase in Lp(a) levels on each outcome. Results Genetically predicted Lp(a) levels associated with significantly increased risk of all‐cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02–1.07], P =2.05×10 −4 ) and large artery atherosclerotic stroke (OR, 1.23 [95% CI, 1.14–1.33], P =3.54×10 −7 ). There was a nominal association with cardioembolic stroke (OR, 1.07 [95% CI, 1.01–1.13], P =0.02), and no evidence for association with small vessel stroke (OR, 0.98 [95% CI, 0.91–1.06], P =0.60). Associations with early‐onset stroke were similar, though with a greater magnitude of association for large artery atherosclerotic stroke (OR, 1.37 [95% CI, 1.15–1.64], P =5.58×10 −4 ). Analyses of secondary outcomes paralleled these findings, including significant associations of genetically predicted Lp(a) with carotid plaque and atrial fibrillation, nominal associations with lobar hemorrhage and autopsy‐confirmed microinfarcts, and null associations with cerebral small vessel disease phenotypes. Conclusions Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)‐lowering stroke prevention trials.