BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic 
inflammation that is strongly associated with cardiovascular disease. We sought 
to identify genetic variants that are associated with CRP levels.
METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 
66 185 participants from 15 population-based studies. We sought replication for 
the genome-wide significant and suggestive loci in a replication panel 
comprising 16 540 individuals from 10 independent studies. We found 18 
genome-wide significant loci, and we provided evidence of replication for 8 of 
them. Our results confirm 7 previously known loci and introduce 11 novel loci 
that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, 
LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, 
and IRF1) or that reside in regions previously not known to play a role in 
chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found 
a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A 
weighted genetic risk score that was developed to summarize the effect of risk 
alleles was strongly associated with CRP levels and explained ≈5% of the trait 
variance; however, there was no evidence for these genetic variants explaining 
the association of CRP with coronary heart disease.
CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our 
study highlights immune response and metabolic regulatory pathways involved in 
the regulation of chronic inflammation.