C-reactive protein and all-cause mortality--the Copenhagen City Heart Study.
OBJECTIVE
We tested whether elevated levels of C-reactive protein is robustly and causally associated with all-cause mortality.


RESULTS
We studied 10 388 white persons from the general population. During 16 years 3124 persons died. We measured baseline high-sensitivity C-reactive protein and fibrinogen levels and genotyped for four C-reactive protein polymorphisms and two apolipoprotein E polymorphisms. Levels of C-reactive protein >3 mg/L vs. <1 mg/L associated with a multi-factorially adjusted two-fold increased risk of all-cause mortality. Stratifying C-reactive protein into tertiles, quintiles, or octiles resulted in step-by-step increased risk of all-cause mortality, even after fibrinogen adjustment. Finally, genetically elevated C-reactive protein levels associated with a causal hazard ratio of 0.94 (95% CI: 0.64-1.39) for all-cause mortality per doubling of C-reactive protein levels on instrumental variable analysis, for which the corresponding hazard ratio on Cox regression for a doubling in measured plasma C-reactive protein levels was 1.25 (1.21-1.29). As a positive control, a doubling in genetically elevated cholesterol levels via apolipoprotein E associated with a hazard ratio of 6.3 (1.8-22) for all-cause mortality.


CONCLUSIONS
A single C-reactive protein measurement robustly associates with increased risk of all-cause mortality; however, this does not appear to be a causal association. Therefore, elevated C-reactive protein levels more likely are a marker of hidden, potentially fatal inflammatory disease.
Zacho
Jeppe
J
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
Tybjaerg-Hansen
Anne
A
Nordestgaard
Børge G
BG
D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002423:Cause of Death; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005838:Genotype; D006331:Heart Diseases / Q000097:blood / Q000235:genetics / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
D015415:Biomarkers; D005340:Fibrinogen; D002097:C-Reactive Protein