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Published on: March 29, 2024
Bidirectional causal relationship between hypercholesterolemia and ischemic heart disease: a Mendelian randomization
Ying Jiang1, Wenpeng Yu1, Jianliang Zhou2
1Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Insights
This study used genetic data to show that high cholesterol (hypercholesterolemia) and ischemic heart disease (IHD) have a two-way causal link. Shared genes like APOE were identified, suggesting new treatment targets for both conditions.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disorders
- Epidemiology
Background:
- Ischemic heart disease (IHD) is a major global health concern.
- Hypercholesterolemia, characterized by high cholesterol levels, is linked to IHD.
- The precise causal relationship between hypercholesterolemia and IHD requires further elucidation.
Purpose of the Study:
- To investigate the bidirectional causal relationship between hypercholesterolemia and IHD using genetic evidence.
- To identify shared genetic factors contributing to both conditions.
- To explore potential therapeutic targets based on genetic insights.
Main Methods:
- A two-sample Mendelian randomization (MR) analysis was performed.
- Genetic variants associated with hypercholesterolemia and IHD were utilized.
- Multiple statistical methods (MR-Egger, IVW, Weighted Median) and sensitivity analyses were employed.
- Genetic co-localization analysis was conducted to identify shared genes.
Main Results:
- A significant bidirectional causal relationship was confirmed between hypercholesterolemia and IHD.
- Increased odds of IHD were associated with hypercholesterolemia (OR=2.27).
- Increased odds of hypercholesterolemia were associated with IHD (OR=1.80).
- Four genes (CELSR2, PCSK9, LPA, APOE) were identified as co-localized and potentially implicated in both conditions.
Conclusions:
- Mendelian randomization provides genetic evidence for a causal link between hypercholesterolemia and IHD.
- The findings support a bidirectional relationship, with IHD potentially influencing hypercholesterolemia.
- Co-localization analysis suggests shared genetic causal variants, offering targets for novel therapeutic strategies.
Background:
Ischemic Heart Disease (IHD) is a leading cause of morbidity and mortality worldwide. Hypercholesterolaemia, a metabolic syndrome distinguished by elevated cholesterol levels, is positively correlated with IHD, yet the precise causal relationship between these two health conditions remains to be clearly defined.
Methods:
We conducted a two-sample MR analysis using genetic variants associated with hypercholesterolemia and IHD. Various statistical techniques including MR-Egger, Weighted Median, Inverse Variance Weighted (IVW), Simple Mode, and Weighted Mode were employed. We also performed sensitivity analyses to assess pleiotropy, heterogeneity, and influence of individual SNPs. Furthermore, genetic co-localization analysis was performed to identify shared genes between hypercholesterolemia and IHD.
Results:
Our MR study illuminated a bidirectional causal relationship between hypercholesterolaemia and ischaemic heart disease. Utilising the IVW with multiplicative random effects, upon considering IHD as the outcome, we identified an OR of 2.27 (95% CI: 1.91-2.70, p = 1.68 × 10-20). Conversely, when hypercholesterolaemia was viewed as the outcome, the OR detected was 1.80 (95% CI: 1.58-2.05, p = 2.79 × 10-19). These findings remained consistent across various MR methods and sensitivity analyses. Additionally, our research pinpointed four co-localised genes CELSR2, PCSK9, LPA, and APOE as integral candidates implicated in the pathogenesis of both conditions, thereby suggesting shared common genetic causal variants and offering potential targets for innovative therapeutic strategies.
Conclusion:
bidirectional MR studies reveal genetic evidence of a potential causal link between hypercholesterolaemia and IHD. Notably, these findings also lend credence to the less traditional hypothesis that IHD may instigate hypercholesterolaemia episodes. Moreover, co-localisation analyses intimate the presence of shared genetic causal variants, paving the way for the development of new therapeutic strategies.
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