Genome-Wide Association: Multiple Loci for C-Reactive Protein Levels

(Circulation. 2011;0:CIRCULATIONAHA.110.948570.)
© 2011 American Heart Association, Inc. 

Original Article

Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Abbas Dehghan, MD, PhD; From the Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands (A.D., M.K., A.H., C.M.v.D., J.C.M.W.);
Correspondence to Jacqueline C.M. Witteman, PhD, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands (E-mail j.witteman@erasmusmc.nl); or Daniel I. Chasman, PhD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02215 (E-mail dchasman@rics.bwh.harvard.edu).
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 soughtreplication 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, andBCL7B). We found a significant interaction of body mass index with LEPR (P<2.9x10^–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 explainingthe 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.