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C-Reactive Protein Levels and Risk of Cardiovascular Diseases: A Two-Sample Bidirectional Mendelian Randomization
Annapurna Kuppa1, Himi Tripathi1, Ahmed Al-Darraji1
1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Insights
Elevated C-reactive protein (CRP) is linked to hypertensive heart disease (HHD) risk. This Mendelian randomization study found no significant causal link between CRP and other cardiovascular diseases, suggesting CRP may be a specific biomarker for HHD.
Area of Science:
- Cardiovascular Epidemiology
- Genetic Epidemiology
- Inflammation Biomarkers
Background:
- Elevated C-reactive protein (CRP) indicates inflammation and is a potential cardiovascular disease (CVD) risk factor.
- Observational studies on the CRP-CVD association are inconclusive, necessitating robust causal inference methods.
- Understanding the causal role of CRP in specific CVD subtypes is crucial for clinical applications.
Purpose of the Study:
- To investigate the causal relationship between C-reactive protein (CRP) and various cardiovascular diseases (CVDs) using a bidirectional Mendelian randomization (MR) approach.
- To assess the potential of CRP as a causal risk factor for specific CVD subtypes, including hypertensive heart disease (HHD).
- To evaluate potential reverse causation between CRP and CVD.
Main Methods:
- A two-sample bidirectional Mendelian randomization (MR) study utilizing publicly available Genome-Wide Association Study (GWAS) summary statistics.
- Selection of instrumental variables (IVs) based on rigorous criteria, with F-statistics used to assess IV strength.
- Assessment of horizontal pleiotropy and heterogeneity using MR-Egger intercept and Cochran's Q-test; outlier correction via MR-PRESSO and Multivariable MR.
Main Results:
- A statistically significant causal effect of CRP on the risk of hypertensive heart disease (HHD) was observed.
- No significant causal relationship was found between CRP and the risk of myocardial infarction, coronary artery disease, heart failure, or atherosclerosis.
- Sensitivity analyses, including outlier exclusion, confirmed the primary findings, and no evidence of reverse causation was detected.
Conclusions:
- C-reactive protein (CRP) may causally increase the risk of hypertensive heart disease (HHD).
- The study did not establish a causal link between CRP and other major cardiovascular diseases, challenging its role as a universal CVD biomarker.
- Further MR studies are warranted to validate CRP's role as a specific clinical biomarker for HHD.
Abstract:
Elevated C-reactive protein (CRP) levels are an indicator of inflammation, a major risk factor for cardiovascular disease (CVD). However, this potential association in observational studies remains inconclusive. We performed a two-sample bidirectional Mendelian randomization (MR) study using publicly available GWAS summary statistics to evaluate the relationship between CRP and CVD. Instrumental variables (IVs) were carefully selected, and multiple approaches were used to make robust conclusions. Horizontal pleiotropy and heterogeneity were evaluated using the MR-Egger intercept and Cochran's Q-test. The strength of the IVs was determined using F-statistics. The causal effect of CRP on the risk of hypertensive heart disease (HHD) was statistically significant, but we did not observe a significant causal relationship between CRP and the risk of myocardial infarction, coronary artery disease, heart failure, or atherosclerosis. Our primary analyses, after performing outlier correction using MR-PRESSO and the Multivariable MR method, revealed that IVs that increased CRP levels also increased the HHD risk. However, after excluding outlier IVs identified using PhenoScanner, the initial MR results were altered, but the sensitivity analyses remained congruent with the results from the primary analyses. We found no evidence of reverse causation between CVD and CRP. Our findings warrant updated MR studies to confirm the role of CRP as a clinical biomarker for HHD.
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