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. 2009 Jul 1;302(1):37-48.
doi: 10.1001/jama.2009.954.

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

Paul Elliott  1 , John C Chambers, Weihua Zhang, Robert Clarke, Jemma C Hopewell, John F Peden, Jeanette Erdmann, Peter Braund, James C Engert, Derrick Bennett, Lachlan Coin, Deborah Ashby, Ioanna Tzoulaki, Ian J Brown, Shahrul Mt-Isa, Mark I McCarthy, Leena Peltonen, Nelson B Freimer, Martin Farrall, Aimo Ruokonen, Anders Hamsten, Noha Lim, Philippe Froguel, Dawn M Waterworth, Peter Vollenweider, Gerard Waeber, Marjo-Riitta Jarvelin, Vincent Mooser, James Scott, Alistair S Hall, Heribert Schunkert, Sonia S Anand, Rory Collins, Nilesh J Samani, Hugh Watkins, Jaspal S Kooner
Affiliations

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

Paul Elliott et al. JAMA. .

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 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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Figures

Figure 1
Figure 1
Manhattan plot of results from the combined analysis of genome-wide association data (9 cohorts)
Figure 2
Figure 2
Results of Mendelian randomisation experiment of rs7553007 in the CRP locus (present study), with rs1130864 and rs1205 from published studies, with CHD, among 28,112 cases and 100,823 controls. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP
Figure 3
Figure 3
Meta-analysis of associations of SNPs rs1130864 and rs1205 with CRP levels, CRP levels with CHD, and SNPs with CHD, in prospective studies where all three analyses have been reported. (a) Associations of SNPs rs1130864 and rs1205 with CRP levels. Effects are given as % change (95% Confidence Intervals) per minor allele (rs1205) and per major allele (rs1130864). (b) Associations of CRP levels with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP. (c) Associations of SNPs rs1130864 and rs1205 with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP
Figure 3
Figure 3
Meta-analysis of associations of SNPs rs1130864 and rs1205 with CRP levels, CRP levels with CHD, and SNPs with CHD, in prospective studies where all three analyses have been reported. (a) Associations of SNPs rs1130864 and rs1205 with CRP levels. Effects are given as % change (95% Confidence Intervals) per minor allele (rs1205) and per major allele (rs1130864). (b) Associations of CRP levels with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP. (c) Associations of SNPs rs1130864 and rs1205 with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP
Figure 3
Figure 3
Meta-analysis of associations of SNPs rs1130864 and rs1205 with CRP levels, CRP levels with CHD, and SNPs with CHD, in prospective studies where all three analyses have been reported. (a) Associations of SNPs rs1130864 and rs1205 with CRP levels. Effects are given as % change (95% Confidence Intervals) per minor allele (rs1205) and per major allele (rs1130864). (b) Associations of CRP levels with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP. (c) Associations of SNPs rs1130864 and rs1205 with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP
Figure 4
Figure 4
Meta-analysis of the relationship of CRP levels with CHD from prospective observational studies. Effects are given as Odds Ratios (95% Confidence Intervals) per 20% lower CRP Footnote to Figure 4. Random effects estimate presented in Figure, fixed effects estimate: OR 0.951 (95% CI, 0.945-0.957). For cohort studies, number of ‘controls’ represents the number of event-free individuals. Number of controls was not available for ARIC (Ref 65). *Case-cohort **Cohort ***Nested case-control
Figure 5
Figure 5
Associations of SNPs in LEPR (rs6700896), IL6R (rs4537545), HNF1A (rs1183910) loci and APOE-CI-CII (rs4420638) cluster in the genetic association study with CHD. Effects are given as Odds Ratios (95% Confidence Intervals) per copy of minor allele
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References

    1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;349(9061):1269–76. - PubMed
    1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95. - PubMed
    1. Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med. 2005;2(1):29–36. - PubMed
    1. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004;350(14):1387–97. - PubMed
    1. Shah T, Casas JP, Cooper JA, et al. Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts. Int J Epidemiol. 2009;38(1):217–31. - PMC - PubMed

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