期刊
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
卷 302, 期 1, 页码 37-48出版社
AMER MEDICAL ASSOC
DOI: 10.1001/jama.2009.954
关键词
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资金
- INSERM
- CNAMTS
- Lilly
- Novartis Pharma
- Sanofi-Aventis
- Association Diabete Risque Vasculaire
- Federation Francaise de Cardiologie
- La Fondation de France
- ALFEDIAM
- ONIVINS
- Ardix Medical
- Bayer Diagnostics
- Becton Dickinson
- Cardionics
- Merck Sante
- Novo Nordisk
- Pierre Fabre
- Roche
- Topcon
- European Union [EURODIA LSHM-CT-2006-518153]
- GlaxoSmithKline
- Deutsche Forschungsgemeinschaft
- Deutsche Herzstiftung
- National Genome Research Network 2 of the German Federal Ministry of Education and Research
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Ontario
- International Clinical Epidemiology Network (INCLEN)
- Chile, Universidad de la Frontera, Sociedad Chilena de Cardiologia Filial Sur
- Colombia, Colciencias, Ministerio de Salud
- Croatia, CroatianMinistry of Science and Technology
- Guatemala, Liga Guatemalteca del Corazon
- Hungary, Astra Hassle, National Health Science Council, George Gabor Foundation
- Iran, Iran Ministry of Health
- Italy, Boehringer-Ingelheim
- Japan, Sankyo Pharmaceutical Co
- Banyu Pharmaceutical Co, Astra Japan
- Kuwait, Endowment Fund for Health Development in Kuwait
- Pakistan, ATCO Laboratories
- Philippines, Philippine Council for Health Research and Development
- Pfizer Philippines Foundation, Inc
- Astra Pharmaceuticals Inc
- Astra Fund for Clinical Research and Continuing Medical Education
- Pharmacia and Upjohn Inc
- Poland, Foundation PROCLINICA
- Singapore, Singapore National Heart Association
- South Africa, Medical Research Council of South Africa
- Warner-Parke-Davis Pharmaceuticals
- Aventis
- Swedish State under the LUA agreement
- Swedish Heart and Lung Foundation
- Thailand, Heart Association of Thailand
- Thailand Research Fund
- British Heart Foundation
- Medical Research Council
- Cancer Research UK
- Tobacco Products Research Trust
- Giorgi-Cavaglieri Foundation
- Swiss National Science Foundation [3100AO-116323/1]
- Universite de Lausanne, Lausanne, Switzerland.
- British Heart Foundation [SP/04/002]
- National Heart, Lung, and Blood Institute [5R01HL087679-02]
- Medical Research Council of the United Kingdom
- European Birth Life-Course Study
- European Commission [QLG1-CT2000-01643]
- Biocenter Oulu of University of Oulu
- Academy of Finland
- National Institute of Mental Health [1RL1MH083268-01]
- EC Sixth Framework Programme [LSHM33 CT-2007-037273]
- Wellcome Trust
- MRC [G0700931, G0600331, G0601966, G0801056, MC_U137686857] Funding Source: UKRI
- Medical Research Council [G0600331, G0700931, MC_U137686857, G0801056, G0601966, G0801056B] Funding Source: researchfish
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. JAMA. 2009;302(1):37-48
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