Aims: Circulating C-reactive protein is associated with future cardiovascular events. The causal role of C-reactive protein in the development of atherosclerosis remains controversial.
Methods and results: We analysed the association between three genetic polymorphisms (PM) (-717C>T, rs2794521; +1059G>C, rs1800947; +1444C>T, rs1130864) at the C-reactive protein locus and related haplotypes with both circulating C-reactive protein and angiographic coronary artery disease (CAD). The concentration of C-reactive protein was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the minor alleles of the +1059G>C (rs1800947) and the +1444C>T PM (rs1130864) were associated with decreased and increased concentrations of C-reactive protein, respectively. Haplotypes 1 and 4 decreased, and haplotype 2 increased C-reactive protein, whereas haplotype 3 had no appreciable effect. None of the genetic variants affecting circulating C-reactive protein was consistently associated with the prevalence of angiographic CAD.
Conclusion: A causal role of C-reactive protein in the development of CAD would require that genetic PM resulting in long-term modulation of the concentration of C-reactive protein be themselves associated with CAD. We were not able to detect such a relationship, which can be attributed to either a very small genetic effect size or the relationship between C-reactive protein and cardiovascular events may reflect confounding and reverse causation.