Associations between lipoproteins and risk of ischemic stroke: a systematic review and meta-analysis of Mendelian randomization studies

Objective To systematically evaluate the causal effects of lipoproteins on ischemic stroke (IS) through a systematic review and meta-analysis of Mendelian randomization (MR) studies. Methods A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to identify MR studies investigating the relationship between lipoproteins and IS, covering all publications up to November 2024. Relevant data were extracted, followed by a quality assessment. Meta-analyses were performed using RevMan software, with evaluations of heterogeneity and publication bias. Results A total of 442 studies were evaluated, and 10 were included. Our meta-analysis showed a significant positive correlation between LDL and IS (OR 1.09, 95% CI 1.07–1.12; p < 0.001, I 2 = 0), apoB and IS (OR 1.08, 95% CI 1.02–1.14; p = 0.006, I 2 = 60%), VLDL and IS (OR 1.09, 95% CI 1.01–1.18; p = 0.03). In contrast, apoA1 was significantly negatively associated with IS (OR 0.93, 95% CI 0.89–0.96; p < 0.001, I 2 = 38%). Interestingly, although the association between Lp(a) and IS was not statistically significant (OR 1.01, 95% CI 0.99–1.02; p = 0.26, I 2 = 57%), combined non-HDL lipoproteins were positively associated with IS (OR 1.03, 95% CI 1.01–1.06; p < 0.001, I 2 = 93.6%). In contrast, HDL lipoproteins was significantly negatively associated with IS (OR 0.93, 95% CI 0.89–0.97; p < 0.001, I 2 = 58%). The funnel plot appears generally symmetrical and sensitivity analyses confirmed the robustness of the findings for LDL, apoA1, apoB, HDL, and total cholesterol in relation to IS. Conclusion This meta-analysis provides evidence for a causal relationship between various lipoproteins and ischemic stroke. Most non-HDL lipoproteins (LDL, VLDL, apoB) are associated with an increased risk of IS, while HDL and apoA1 appear to confer a protective effect. The role of Lp(a) in IS remains inconclusive and warrants further investigation. Systematic review registration https://www.crd.york.ac.uk/PROSPERO , CRD42024617825.