Causal Effect of Lp(a) [Lipoprotein(a)] Level on Ischemic Stroke and Alzheimer Disease: A Mendelian Randomization Study.

Abstract

Background and Purpose- Stroke and Alzheimer disease are 2 major causes of neurological disability in aged people and shared overlapping predictors. In recent prospective studies, high Lp(a) [lipoprotein(a)] level is associated with high risk of stroke but low risk of Alzheimer disease. Whether this reflects a causal association remains to be established. The aim of this study is to examine the causal associations of Lp(a) concentrations on ischemic stroke, ischemic stroke subtypes, and Alzheimer disease. Methods- We used 9 single-nucleotide polymorphisms associated with Lp(a) concentrations as instrumental variables. Summary-level data on ischemic stroke and its subtypes were obtained from the Multiancestry Genome-Wide Association Study of Stroke consortium with European individuals ≤446 696 individuals. Summary-level data on Alzheimer disease were obtained from the International Genomics of Alzheimer Project With European individuals ≤54 162 individuals. Two-sample Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches, and MR-Egger regression was used to explore pleiotropy. Results- Genetically predicted 1-SD log-transformed increase in Lp(a) concentrations was associated with a substantial increase in risk of large artery stroke (odds ratio, 1.20; 95% CI, 1.11-1.30; P<0.001) and a reduce in risk of small vessel stroke (odds ratio, 0.92; 95% CI, 0.88-0.97; P=0.001) and Alzheimer disease (odds ratio, 0.94; 95% CI, 0.91-0.97; P<0.001) using inverse-variance weighted method. No significant association was observed for total ischemic stroke or cardioembolic stroke. MR-Egger indicated no evidence of pleiotropic bias. Results were broadly consistent in sensitivity analyses using penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches accounting for potential genetic pleiotropy or outliers. Conclusions- This study provides evidence to support that high Lp(a) concentrations was causally associated with an increased risk of large artery stroke but a decreased risk of small vessel stroke and Alzheimer disease. The mechanism underlying the double-edged sword effect of Lp(a) concentrations on neurological system requires further investigation.

• Authors: Yuesong Pan, Hao Li, Yilong Wang, Xia Meng, Yongjun Wang
• Journal: Stroke (Stroke) Vol. 50 Issue 12 Pg. 3532-3539 (12 2019) ISSN: 1524-4628 [Electronic] United States
• PMID: 31597550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoprotein(a)

Topics

• Alzheimer Disease (epidemiology, genetics)
• Brain Ischemia (classification, epidemiology, genetics)
• Causality
• Cerebral Arteries
• Humans
• Lipoprotein(a) (genetics, metabolism)
• Mendelian Randomization Analysis
• Microvessels
• Polymorphism, Single Nucleotide
• Stroke (classification, epidemiology, genetics)
• White People (genetics)