Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population:
Monica G Rolver1,2, Frida Emanuelsson1,2, Børge G Nordestgaard1,2,1,3
1Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte, Borgmester Ib Juuls Vej 1, Herlev, 2730, Denmark.
Insights
High C-reactive protein (CRP) and hyperglycemia predict ischemic heart disease (IHD) and cardiovascular disease (CVD) death. However, this study found no causal link between CRP and glucose levels, suggesting glucose-lowering treatments may not directly reduce inflammation.
Area of Science:
- Cardiovascular Epidemiology
- Inflammation Research
- Metabolic Disease
Background:
- Low-grade inflammation (measured by C-reactive protein - CRP) and hyperglycemia are potential risk factors for ischemic heart disease (IHD) and cardiovascular disease (CVD) death.
- The causal relationship between CRP and hyperglycemia remains unclear in the general population.
Purpose of the Study:
- To investigate the independent and combined contributions of CRP, hyperglycemia, and type 2 diabetes to IHD and CVD death risk.
- To determine if hyperglycemia and high CRP are causally related.
Main Methods:
- Utilized observational and bidirectional Mendelian randomization (MR) analyses.
- Included data from large population studies (Copenhagen General Population Study, Copenhagen City Heart Study) and consortia (CHARGE, MAGIC).
- Employed one-sample and two-sample MR to assess causality between CRP and glucose.
Main Results:
- Elevated plasma CRP and glucose levels were associated with increased risk of IHD and CVD death.
- Individuals with both type 2 diabetes and high CRP (≥2 mg/L) exhibited significantly higher cumulative incidences of IHD and CVD death.
- Observational data showed a link between CRP and glucose, but MR analyses did not support a causal effect in either direction.
Conclusions:
- Elevated plasma CRP and glucose are significant predictors of IHD and CVD mortality in the general population.
- No evidence of a causal relationship between CRP and glucose was found, suggesting pharmacological glucose-lowering interventions may not directly impact low-grade inflammation.
Objective:
To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related.
Research Design And Methods:
Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC.
Results:
Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (β-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)).
Conclusions:
Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.
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