Abstract A015: Genetically Predicted Levels of Lipoprotein(a) and Risk of Cerebrovascular Disease

Background: Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein and a target of investigational therapies. Using a Mendelian randomization (MR) study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and endophenotypes. 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 twelve related cerebrovascular phenotypes. Lp(a) was proxied using two LPA genetic variants (rs10455872 and rs3798220) that explain 36% of the variance in Lp(a) levels. We performed MR analyses to estimate the association of a genetically predicted 50 mg/dL increase in Lp(a) levels on each outcome. Results: Genetically predicted Lp(a) levels associated with significantly increased risk of all-cause ischemic stroke (OR 1.05, 95% confidence interval [CI] 1.03-1.08, P =2.05x10 -4 ) and large artery atherosclerotic stroke (OR 1.26, 95% confidence interval [CI] 1.15-1.37, P =3.54x10 -7 ). There was a nominal association with cardioembolic stroke (OR 1.07, 95% CI 1.01-1.14, P =0.02), and no evidence for association with small vessel stroke (OR 0.98, 95% CI 0.90-1.06, P =0.60). Associations with early-onset stroke were similar, though with a greater magnitude of association for large artery atherosclerotic stroke (OR 1.42, 95% CI 1.16-1.72, P =5.58x10 -4 ). Secondary outcomes paralleled these findings, including significant associations with carotid plaque and atrial fibrillation, nominal associations with autopsy-confirmed microinfarcts, and null associations with small vessel disease markers. Although the association with intracerebral hemorrhage was null (OR 0.94, 95% CI 0.81-1.08, P =0.37), we found a nominal association with lobar hemorrhage (OR 1.90, 95% CI 1.00-3.61, P =0.05) and directionally concordant but nonsignificant associations with lobar microbleeds and autopsy-confirmed cerebral amyloid angiopathy. Conclusions: Lp(a) is strongly associated with ischemic stroke due to large artery atherosclerosis, supporting prioritization of patients with atherosclerotic disease in Lp(a)-lowering stroke prevention trials. Potential links to lobar hemorrhage and cerebral amyloid angiopathy warrant further investigation.