GeneticLociAssociatedWithC-ReactiveProtein Levels and Risk of Coronary Heart Disease

Context Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart diseaseor merely a marker of underlying atherosclerosis is uncertain. Objective To investigate association of genetic loci with CRP levels and risk of coro- nary heart disease. Design, Setting, and Participants We first carried out a genome-wide associa- tion (n=17 967) and replication study (n=13 615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomizationstudy of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28 112 cases and 100 823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of obser- vational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart diseaseamong 14 365 cases and 32 069 controls. Main Outcome Measure Risk of coronary heart disease. Results Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (�14.8%; 95% confidence interval (CI), �17.6% to �12.0%; P=6.210 �22 ), rs4537545 in IL6R (�11.5%; 95% CI, �14.4% to �8.5%; P=1.310 �12 ). Association of SNP rs7553007 in the CRP lo- cus with coronary heart diseasegave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomizationstudy of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease(z score, �3.45; P.001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. Conclusion The lack of concordance between the effect on coronary heart diseaserisk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.