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C-reactive protein and prospective cardiometabolic risk: observational and Mendelian randomization study of ischemic
Monica G Rolver1,2, Frida Emanuelsson1,2, Børge G Nordestgaard2,3,4
1Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Insights
Elevated C-reactive protein (CRP) predicts higher risk of ischemic stroke and death in observational studies. However, genetic analyses found no causal link between CRP and these outcomes, suggesting inflammation is a marker, not a cause.
Area of Science:
- Cardiovascular Epidemiology
- Inflammation Biomarkers
- Genetic Epidemiology
Background:
- Elevated C-reactive protein (CRP) is linked to systemic inflammation and cardiometabolic diseases.
- The predictive value of CRP for ischemic stroke and all-cause mortality in the general population requires further investigation.
- Understanding the causal role of CRP in these outcomes is crucial for clinical risk assessment.
Purpose of the Study:
- To determine if plasma CRP concentrations predict ischemic stroke and all-cause death risk.
- To investigate the potential causal effect of elevated plasma CRP on ischemic stroke and all-cause death.
Main Methods:
- Combined observational and Mendelian randomization (MR) analyses.
- Utilized large population cohorts: Copenhagen City Heart Study and Copenhagen General Population Study (n=113,491).
- Employed two-sample MR in up to 575,531 individuals from multiple consortia (CHARGE CIWG, UKBB, FinnGen, MEGASTROKE).
Main Results:
- Observationally, higher CRP concentrations were associated with significantly increased risk of ischemic stroke (HR 1.51) and all-cause death (HR 1.69).
- Individuals with CRP ≥ 2 mg/L had 57% higher cumulative incidence of ischemic stroke and 62% higher all-cause death by age 80.
- One- and two-sample MR analyses did not support a causal effect of CRP on ischemic stroke or all-cause death (ORs ≈ 1.01).
Conclusions:
- Elevated CRP concentrations above the population median (1.4 mg/L) are predictive of ischemic stroke and all-cause death risk.
- No causal genetic effect of C-reactive protein on the risk of stroke or all-cause death was identified.
- CRP appears to be a marker of underlying risk rather than a direct causal factor for these outcomes.
Background And Objectives:
Elevated C-reactive protein (CRP) is a well-established marker of low-grade systemic inflammation often accompanying cardiometabolic diseases like type 2 diabetes. We sought to determine if plasma CRP concentrations can be used as a predictive marker of risk for ischemic stroke and all-cause death in the general population, and to investigate whether elevated plasma CRP has a causal effect on ischemic stroke and all-cause death.
Methods:
Observational and one-sample Mendelian randomization analyses were performed in 113,491 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study. Two-sample Mendelian randomization analyses were performed in up to 575,531 individuals with publicly available data from the CHARGE CIWG, UKBB, FinnGen, and MEGASTROKE.
Results:
Observationally in the Copenhagen studies, higher CRP concentrations associated with stepwise higher risk of ischemic stroke and all-cause death with the highest hazard ratios of 1.51(95% confidence interval: 1.34, 1.71) and 1.69(1.60, 1.79), respectively. The cumulative incidence of ischemic stroke at age 72 was 57% higher and the cumulative incidence of all-cause death at age 80 was 62% higher in individuals with a plasma CRP ≥ 2 mg/L compared to individuals with a plasma CRP < 2 mg/L. One- and two-sample Mendelian randomization analyses did not support a causal effect of CRP on risk of ischemic stroke, nor of CRP on risk of all-cause death, with odds ratios in studies combined of 1.01(0.98, 1.05) and 1.01(0.98, 1.05), respectively.
Conclusion:
In this observational and one- and two-sample Mendelian randomization study, we found that elevated CRP concentrations above the population median of 1.4 mg/L predicted risk of ischemic stroke and all-cause death. There was no causal genetic effect of C-reactive protein on risk of stroke or all-cause death.
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