Abstract
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.