Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

TitleGenetic Loci associated with C-reactive protein levels and risk of coronary heart disease.
Publication TypeJournal Article
Year of Publication2009
AuthorsElliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J, Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S, McCarthy MI, Peltonen L, Freimer NB, Farrall M, Ruokonen A, Hamsten A, Lim N, Froguel P, Waterworth DM, Vollenweider P, Waeber G, Jarvelin M-R, Mooser V, Scott J, Hall AS, Schunkert H, Anand SS, Collins R, Samani NJ, Watkins H, Kooner JS
JournalJAMA
Volume302
Issue1
Pagination37-48
Date Published2009 Jul 1
ISSN1538-3598
KeywordsAdult, Aged, C-Reactive Protein, Coronary Disease, Female, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Molecular Epidemiology, Polymorphism, Single Nucleotide, Risk Factors
Abstract

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 disease or merely a marker of underlying atherosclerosis is uncertain.

OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease.

DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (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 randomization study 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 observational 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 disease among 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 = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study 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 disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

DOI10.1001/jama.2009.954
Alternate JournalJAMA
PubMed ID19567438
PubMed Central IDPMC2803020
Grant List089061 / / Wellcome Trust / United Kingdom
1RL1MH083268-01 / MH / NIMH NIH HHS / United States
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
G0600331 / / Medical Research Council / United Kingdom
G0601966 / / Medical Research Council / United Kingdom
G0700931 / / Medical Research Council / United Kingdom
G0801056 / / Medical Research Council / United Kingdom
LSHM33 CT-2007-037273 / / British Heart Foundation / United Kingdom
MC_U137686857 / / Medical Research Council / United Kingdom
SP/04/002 / / British Heart Foundation / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Department of Health / United Kingdom
/ / Cancer Research UK / United Kingdom
/ / Wellcome Trust / United Kingdom