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Paul Elliott, FRCP; John C. Chambers, PhD; Weihua Zhang, PhD; Robert Clarke, MD; Jemma C. Hopewell, PhD; John F. Peden, PhD; Jeanette Erdmann, PhD; Peter Braund, MSc; James C. Engert, PhD; Derrick Bennett, PhD; Lachlan Coin, PhD; Deborah Ashby, PhD; Ioanna Tzoulaki, PhD; Ian J. Brown, PhD; Shahrul Mt-Isa, BSc; Mark I. McCarthy, FRCP; Leena Peltonen, MD, PhD; Nelson B. Freimer, MD; Martin Farrall, FRCPath; Aimo Ruokonen, MD, PhD; Anders Hamsten, MD; Noha Lim, PhD; Philippe Froguel, MD; Dawn M. Waterworth, PhD; Peter Vollenweider, MD; Gerard Waeber, MD; Marjo-Riitta Jarvelin, MD; Vincent Mooser, MD; James Scott, FRS; Alistair S. Hall, FRCP; Heribert Schunkert, MD; Sonia S. Anand, MD; Rory Collins, FRCP; Nilesh J. Samani, FRCP; Hugh Watkins, FRCP; Jaspal S. Kooner, FRCP

JAMA. 2009;302(1):37-48.

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.

Author Affiliations: Faculty of Medicine, Imperial College London, London, United Kingdom (Drs Elliott, Chambers, Zhang, Coin, Ashby, Tzoulaki, Brown, Mt-Isa, Ashby, Froguel, Jarvelin, Scott, and Kooner); Institute of Health Science (Dr Jarvelin), Institute of Diagnostics (Dr Ruokonen), and Biocenter Oulu (Dr Jarvelin), University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Oulu (Dr Jarvelin); Clinical Trial Service Unit and Epidemiological Studies Unit (Drs Clarke, Hopewell, Bennett, and Collins), and Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics (Drs Peden, Farrall, and Watkins), University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism and Oxford National Institute for Health Research Biomedical Research Centre, Oxford (Dr McCarthy); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (Dr Peltonen); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (Drs Braund and Samani); Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada (Dr Engert); Leeds Institute for Genetics and Therapeutics, University of Leeds, Leeds, United Kingdom (Dr Hall); Universität zu Lübeck, Lübeck, Germany (Drs Erdmann and Schunkert); Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada (Dr Anand); Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton (Dr Anand); Department of Medicine, CHUV University Hospital, Lausanne, Switzerland (Drs Vollenweider and Waeber); Center for Neurobehavioral Genetics, University of California at Los Angeles (Dr Freimer); Department of Medicine, Karolinska Institutet, Stockholm, Sweden (Dr Hamsten); and Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania (Drs Lim, Waterworth, and Mooser).

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