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

Elliott, Paul, Chambers, John C., Zhang, Weihua, Clarke, Robert, Hopewell, Jemma C., Peden, John F., Erdmann, Jeanette, Braund, Peter, Engert, James C., Bennett, Derrick, Coin, Lachlan, Ashby, Deborah, Tzoulaki, Ioanna, Brown, Ian J., Mt-Isa, Shahrul, McCarthy, Mark I., Peltonen, Leena, Freimer, Nelson B., Farrall, Martin, Ruokonen, Aimo, Hamsten, Anders, Lim, Noha, Froguel, Philippe, Waterworth, Dawn M., Vollenweider, Peter, Waeber, Gerard, Jarvelin, Marjo-Riitta, Mooser, Vincent, Scott, James, Hall, Alistair S., Schunkert, Heribert, Anand, Sonia S., Collins, Rory, Samani, Nilesh J., Watkins, Hugh and Kooner, Jaspal S. (2009) Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA: The Journal of the American Medical Association, 302 1: 37-48. doi:10.1001/jama.2009.954

Author Elliott, Paul
Chambers, John C.
Zhang, Weihua
Clarke, Robert
Hopewell, Jemma C.
Peden, John F.
Erdmann, Jeanette
Braund, Peter
Engert, James C.
Bennett, Derrick
Coin, Lachlan
Ashby, Deborah
Tzoulaki, Ioanna
Brown, Ian J.
Mt-Isa, Shahrul
McCarthy, Mark I.
Peltonen, Leena
Freimer, Nelson B.
Farrall, Martin
Ruokonen, Aimo
Hamsten, Anders
Lim, Noha
Froguel, Philippe
Waterworth, Dawn M.
Vollenweider, Peter
Waeber, Gerard
Jarvelin, Marjo-Riitta
Mooser, Vincent
Scott, James
Hall, Alistair S.
Schunkert, Heribert
Anand, Sonia S.
Collins, Rory
Samani, Nilesh J.
Watkins, Hugh
Kooner, Jaspal S.
Title Genetic loci associated with C-reactive protein levels and risk of coronary heart disease
Journal name JAMA: The Journal of the American Medical Association   Check publisher's open access policy
ISSN 0098-7484
Publication date 2009-07-01
Sub-type Article (original research)
DOI 10.1001/jama.2009.954
Open Access Status
Volume 302
Issue 1
Start page 37
End page 48
Total pages 12
Place of publication Chicago, United States
Publisher American Medical Association
Language eng
Formatted 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 × 10−22), rs4537545 in IL6R (−11.5%; 95% CI, −14.4% to −8.5%; P = 1.3 × 10−12), rs7553007 in the CRP locus (−20.7%; 95% CI, −23.4% to −17.9%; P = 1.3 × 10−38), rs1183910 in HNF1A (−13.8%; 95% CI, −16.6% to −10.9%; P = 1.9 × 10−18), and rs4420638 in APOE-CI-CII (−21.8%; 95% CI, −25.3% to −18.1%; P = 8.1 × 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.

Keyword Genome-wide association
Apparently healthy men
Low-grade inflammation
Nested case control
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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