Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease
Open accessAbstract
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.
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CRP is a predictive biomarker for cardiovascular disease but is not causally related to atherothrombosis.
“other mechanistic studies and Mendelian randomization analyses in large populations suggest that CRP is a predictive biomarker that is not causally related to atherothrombosis”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [164]
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- Authors
- Elliott, P.
- Affiliations
- Imperial College London (GB)
- Corresponding author
- Elliott, Paul
- ORCID
- Elliott, Paul
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2009-07-01
- Volume
- 302
- Issue
- 1
- Pages
- 37
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W1242386148
- Cited by
- 35
- References
- 46
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 6 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 4
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- WOS
- Funders
- National Science Foundation
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Heart and Stroke Foundation of Canada
- McMaster University
- Wellcome Trust (089061)
- Les Laboratories Pierre Fabre
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation (LSHM33 CT-2007-037273, SP/04/002)
- Imperial College London
- European Commission (LSHM-CT-2006-518153)
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Bundesministerium für Bildung und Forschung
- Fédération Française de Cardiologie
- Novo Nordisk
- Thailand Research Fund
- Fondation de France
- Deutsche Herzstiftung
- Oulun Yliopisto
- Université de Lausanne
- Association Diabète Risque Vasculaire
- National Institutes of Health (6r01hl087679-03, 5rl1mh083268-05)
- Novartis Pharma
- Canadian Institutes of Health Research
- Medical Research Council
- National Heart, Lung, and Blood Institute (5R01 HL087679-02, R01 HL087679)
- National Institute of Mental Health (RL1-MH083268, 1RL1MH083268-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- C-reactive protein, coronary artery disease, genetic loci, single nucleotide polymorphisms, plasma CRP levels, Mendelian randomization, causal relationship, IL-6 receptor, HNF1A, leptin receptor, atherosclerosis, inflammation, cardiovascular risk factors
- MeSH terms
- Adult, Aged, C-Reactive Protein, Coronary Disease, Female, Genotype, Humans, Male, Middle Aged, Risk Factors, Meta-Analysis as Topic, Molecular Epidemiology, Polymorphism, Single Nucleotide, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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