A Mendelian Randomization Study of Plasma Homocysteine Levels and Cerebrovascular and Neurodegenerative Diseases
Weishi Liu1,2,3, Luyang Zhang1,2, Shen Li1,2,3
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Insights
High homocysteine (Hcy) levels causally link to a specific type of ischemic stroke, small artery occlusion stroke (SAS). This association may be influenced by blood pressure and type 2 diabetes, but not other cerebrovascular or neurodegenerative diseases.
Area of Science:
- Genetics
- Neurology
- Cardiovascular Science
Background:
- Hyperhomocysteinemia (HHcy), elevated homocysteine (Hcy) levels, is implicated in cerebrovascular and neurodegenerative diseases.
- Understanding the causal relationship between Hcy and these conditions is crucial for targeted interventions.
- Mendelian randomization (MR) offers a robust approach to investigate causality using genetic variants.
Purpose of the Study:
- To investigate the potential causal link between plasma homocysteine levels and cerebrovascular and neurodegenerative diseases.
- To differentiate the association of Hcy with specific subtypes of ischemic stroke and neurodegenerative conditions.
- To identify potential mediating factors influencing the Hcy-disease relationship.
Main Methods:
- A two-sample Mendelian randomization (MR) study design was employed.
- Genetic variants (SNPs) associated with plasma Hcy levels were identified from a large GWAS meta-analysis.
- Inverse variance-weighted (IVW) method was used for primary analysis, with MR-Egger and Cochran's Q tests for pleiotropy and heterogeneity detection.
Main Results:
- Thirteen Hcy-associated SNPs served as instrumental variables.
- A statistically significant causal link was observed between plasma Hcy levels and small artery occlusion stroke (SAS) (OR = 1.329, p = 0.048).
- No significant causal association was found for other ischemic stroke types, transient ischemic attack (TIA), or neurodegenerative diseases. Blood pressure and type 2 diabetes mellitus were identified as potential influencers.
Conclusions:
- Plasma homocysteine levels exhibit a modest causal association with small artery occlusion stroke (SAS).
- The identified link between Hcy and SAS is likely modulated by other risk factors, including blood pressure and type 2 diabetes.
- Homocysteine does not appear to have a causal role in other cerebrovascular or neurodegenerative diseases investigated.
Abstract:
Background: Homocysteine (Hcy) is a toxic amino acid and hyperhomocysteinemia (HHcy) was reported to be associated with both cerebrovascular disease and neurodegenerative disease. Our aim was to assess the causal link between plasma Hcy level and cerebrovascular and neurodegenerative diseases through a Mendelian randomization (MR) study. Methods: A two-sample MR study was performed to infer the causal link. We extracted the genetic variants (SNPs) associated with plasma Hcy level from a large genome-wide association study (GWAS) meta-analysis. The main MR analysis was performed using the inverse variance-weighted method. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to detect the heterogeneity or pleiotropy of our findings. Results: Thirteen Hcy-associated SNPs were selected as instrumental variables. The results showed evidence of a causal link between plasma Hcy level and ischemic stroke (IS) caused by small artery occlusion (SAS, OR = 1.329, 95% CI 1.047-1.612, p = 0.048). Meanwhile, there was no evidence of association between plasma Hcy level and other types of IS, transient ischemic attack (TIA), or neurodegenerative disease. The MR-Egger intercept test indicated no evidence of directional pleiotropy. Results of additional MR analysis indicated that blood pressure (BP) and type 2 diabetes mellitus (T2DM) serve as influencers in the association. Conclusion: The MR study found a little causal link between plasma Hcy level and SAS. The link is likely to be influenced by other risk factors like BP and T2DM.
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