Genetic Loci Influencing C-reactive Protein Levels and Risk of Coronary Heart Disease

By Paul Elliott, J. Chambers, Weihua Zhang, R. Clarke, J. Hopewell, J. Peden, J. Erdmann, P. Braund, J. Engert, D. Bennett and 26 more. Journal of the American Medical Association (JAMA), 2009

643 citations recorded by the source corpus.

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=14,747) 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 randomisation study of the most closely associated 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 five genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (−14.7% [95% Confidence Interval {CI}], −17.5 – −11.9, P=1.6×10−21), rs4537545 in IL6R (−10.8% [95% CI, −13.8 – −7.7], P=5.1×10−11), rs7553007 in CRP locus (−20.7% [95% CI, −23.5 – −17.9], P=3.3×10−38), rs1183910 in HNF1A (−13.6% [95% CI, −16.4 – −10.6], P=1.2×10−17) and rs4420638 in APOE-CI-CII (−21.8% [95% CI, −25.4 – −18.1], P=2.1×10−25). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave odds ratio (OR) 0.98 (95% CI, 0.94 – 1.01) per 20% lower CRP. Our Mendelian randomisation study of variants in the CRP locus showed no association with coronary heart disease: OR 1.00 (95% CI, 0.97 – 1.02) per 20% lower CRP, compared with OR 0.94 (95% CI, 0.94 – 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 – 1.09] per minor allele), rs4537545 in IL6R (OR 0.94 [95% CI, 0.91 – 0.97]) and rs4420638 in the APOE-CI-CII cluster (OR 1.16 [95% CI, 1.12 – 1.21]) were all associated with risk of coronary heart disease. Conclusions: 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.

Subfields: Epidemiology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7ec1405019deff19bf675b755eb9ff226f2b9090

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Citations in the corpus

Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. (2014, neutral): “Nat Rev Immunol 2010 May;10(5):301-316.”
From CRP to IL-6 to IL-1: Moving Upstream To Identify Novel Targets for Atheroprotection (2016, background): “utility of hsCRP as a biomarker, but did not support direct causation.(43,44)”
Five years of GWAS discovery. (2012, background): “This was recently demonstrated by a GWAS of C-reactive protein (CRP) levels; that study found that common variants near the HNF1A gene were associated with variation in CRP.(60) The authors asked whether rare HNF1A mutations that are causal for the Mendelian MODY (MIM 606391) subtype of diabetes are”
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis (2010, background): “At HNF1A, previous studies have reported a cluster of associations, with phenotypes including low-density lipoptrotein (LDL) cholesterol 30 and circulating C-reactive protein levels 31 - 33 , mapping ~18–72 kb from the peak T2D signal.”