European Journal of Epidemiology

, Volume 23, Issue 8, pp 531–540 | Cite as

Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation

  • CRP CHD Genetics CollaborationEmail author


Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP polymorphisms or haplotypes and CHD will be evaluated under different circumstances. This collaboration comprises, at present, about 37,000 CHD outcomes and about 120,000 controls, which should yield suitably precise findings to help judge causality. This work should advance understanding of the relevance of low-grade inflammation to CHD and indicate whether or not CRP itself is involved in long-term pathogenesis.


Coronary heart disease C-reactive protein Genetics Mendelian randomisation 

List of abbreviations


Emerging Risk Factors Collaboration


C-reactive protein


Coronary heart disease


Myocardial infarction


Single nucleotide polymorphism

Supplementary material

10654_2008_9249_MOESM1_ESM.doc (220 kb)
Supplemental Table 1 Provisional list of studies collaborating in the CRP-Coronary Disease Genetics Collaboration as of April 2008 (DOC 220 KB)


  1. 1.
    Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO. III, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499–511.PubMedCrossRefGoogle Scholar
  2. 2.
    Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805–12.PubMedGoogle Scholar
  3. 3.
    Hattori Y, Matsumura M, Kasai K. Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc Res. 2003;58(1):186–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med. 2005;2(1):29–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Paffen E, DeMaat MP. C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res. 2006;71(1):30–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Verma S, Wang CH, Li SH, Dumont AS, Fedak PW, Badiwala MV, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002;106(8):913–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Taylor KE, Giddings JC. van den Berg CW. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol. 2005;25(6):1225–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Pepys MB, Hawkins PN, Kahan MC, Tennent GA, Gallimore JR, Graham D, et al. Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself. Circ Res. 2005;97(11):e97–103.PubMedCrossRefGoogle Scholar
  9. 9.
    Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321(7255):199–204.PubMedCrossRefGoogle Scholar
  10. 10.
    Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, 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.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case–control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144(6):537–47.PubMedGoogle Scholar
  12. 12.
    Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14):973–9.PubMedCrossRefGoogle Scholar
  13. 13.
    The Emerging Risk Factors Collaboration. Analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. Eur J Epidemiol. 2007;22(12):839–69.CrossRefGoogle Scholar
  14. 14.
    Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440(7088):1217–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Keavney B. Genetic epidemiological studies of coronary heart disease. Int J Epidemiol. 2002;31(4):730–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Hingorani A, Humphries S. Nature’s randomised trials. Lancet. 2005;366(9501):1906–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Hingorani AD, Shah T, Casas JP. Linking observational and genetic approaches to determine the role of C-reactive protein in heart disease risk. Eur Heart J. 2006;27(11):1261–3.PubMedCrossRefGoogle Scholar
  19. 19.
    Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol. 2006;35(4):922–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA. 2006;296(22):2703–11.PubMedCrossRefGoogle Scholar
  22. 22.
    Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, Palmer LJ, et al. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet. 2005;366(9501):1954–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Zee RY, Ridker PM. Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis. 2002;162(1):217–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Verzilli CJ, Shah T, Casas JP, Chapman J, Sandhu M, Debenham SL, et al. Bayesian meta analysis of genetic association studies with different sets of markers. Am J Hum Genet 2008; 82(4):859–72Google Scholar
  25. 25.
    Brull DJ, Serrano N, Zito F, Jones L, Montgomery HE, Rumley A, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23(11):2063–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Crawford DC, Sanders CL, Qin X, Smith JD, Shephard C, Wong M, et al. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation. 2006;114(23):2458–65.PubMedCrossRefGoogle Scholar
  27. 27.
    Kardys I, de Maat MP, Uitterlinden AG, Hofman A, Witteman JC. C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam Study. Eur Heart J. 2006;27(11):1331–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Seattle SNPs: National Heart, Lung and Blood Institute’s (NHLBI) Program for genomic application. Accessed 28 May 2008.
  29. 29.
    Ioannidis JP, Gwinn M, Little J, Higgins JP, Bernstein JL, Boffetta P, et al. A road map for efficient and reliable human genome epidemiology. Nat Genet. 2006;38(1):3–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Seminara D, Khoury MJ, O’Brien TR, Manolio T, Gwinn ML, Little J, et al. The emergence of networks in human genome epidemiology: challenges and opportunities. Epidemiology. 2007;18(1):1–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Pai JK, Mukamal KJ, Rexrode KM, Rimm EB. C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies. PLoS ONE. 2008;3(1):e1395.PubMedCrossRefGoogle Scholar
  32. 32.
    Wilson PW, Nam BH, Pencina M, D’Agostino RB Sr, Benjamin EJ, O’Donnell CJ. C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study. Arch Intern Med. 2005;165(21):2473–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Bautista LE, Smeeth L, Hingorani AD, Casas JP. Estimation of bias in nongenetic observational studies using “mendelian triangulation”. Ann Epidemiol. 2006;16(9):675–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;365(9455):224–32.PubMedGoogle Scholar
  35. 35.
    Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res. 2007;16(4):309–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, Chasman DI et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008;82(5):1193–201.PubMedCrossRefGoogle Scholar
  37. 37.
    Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102(10):1082–5.PubMedGoogle Scholar
  38. 38.
    Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3(2):213–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Lowe GD, Rumley A, McMahon AD, Ford I, O’Reilly DS, Packard CJ. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease. Arterioscler Thromb Vasc Biol. 2004;24(8):1529–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  1. 1.CRP CHD Genetics Collaboration Coordinating CentreUniversity of Cambridge CambridgeUK
  2. 2.University College LondonRayne InstituteLondonUK
  3. 3.London School of Hygiene and Tropical MedicineLondonUK
  4. 4.Population Health Research InstituteMcMaster University, Hamilton Health SciencesHamiltonCanada

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