Current Atherosclerosis Reports

, Volume 9, Issue 3, pp 195–203 | Cite as

Genetic determinants of C-reactive protein

  • Jacqueline Suk Danik
  • Paul M. Ridker


C-reactive protein (CRP) levels are a complex phenotype with both genetic and environmental determinants. Recent work has highlighted the impact of genetic variants within the CRP gene as well as other candidate genes, often chosen for their role in the inflammatory pathway, on CRP levels. Emerging work shows the association of such genetic variants in CRP not only to CRP levels, but also to variation of CRP levels in the acute phase response. Work on the relation of genetic variants within CRP to cardiovascular disease has had varied results. Whole-genome association studies to investigate the genetic determinants of CRP levels in an unbiased manner are ongoing.


Single Nucleotide Polymorphism Arterioscler Thromb Vasc Biol Mendelian Randomization Affect Transcription Factor Binding NHLBI Family Heart Study 
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References and Recommended Reading

  1. 1.
    Libby P, Ridker PM: Inflammation and atherothrombosis from population biology and bench research to clinical practice. J Am Coll Cardiol 2006, 48(Suppl 9):A33–46.CrossRefGoogle Scholar
  2. 2.
    Libby P: Inflammation in atherosclerosis. Nature 2002, 420:868–874.PubMedCrossRefGoogle Scholar
  3. 3.
    Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126.PubMedCrossRefGoogle Scholar
  4. 4.
    de Maat MP, Trion A: C-reactive protein as a risk factor versus risk marker. Curr Opin Lipidol 2004, 15:651–657.PubMedCrossRefGoogle Scholar
  5. 5.
    Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000, 342:836–843.PubMedCrossRefGoogle Scholar
  6. 6.
    Pai JK, Pischon T, Ma J, et al.: Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004, 351:2599–2610.PubMedCrossRefGoogle Scholar
  7. 7.
    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, 350:1387–1397.PubMedCrossRefGoogle Scholar
  8. 8.
    Cook NR, Buring JE, Ridker PM: The effect of including c-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006, 145:21–29.PubMedGoogle Scholar
  9. 9.
    Devaraj S, Kumaresan PR, Jialal I: Effect of C-reactive protein on chemokine expression in human aortic endothelial cells. J Mol Cell Cardiol 2004, 36:405–410.PubMedCrossRefGoogle Scholar
  10. 10.
    Verma S, Li SH, Badiwala MV, et al.: Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 2002, 105:1890–1896.PubMedCrossRefGoogle Scholar
  11. 11.
    Pasceri V, Willerson JT, Yeh ET: Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000, 102:2165–2168.PubMedGoogle Scholar
  12. 12.
    Wang CH, Li SH, Weisel RD, et al.: C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003, 107:1783–1790.PubMedCrossRefGoogle Scholar
  13. 13.
    Wolbink GJ, Brouwer MC, Buysmann S, et al.: CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes. J Immunol 1996, 157:473–479.PubMedGoogle Scholar
  14. 14.
    Pepys MB, Hirschfield GM: C-reactive protein: a critical update. J Clin Invest 2003, 111:1805–1812.PubMedCrossRefGoogle Scholar
  15. 15.
    Danenberg HD, Szalai AJ, Swaminathan RV, et al.: Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice. Circulation 2003, 108:512–515.PubMedCrossRefGoogle Scholar
  16. 16.
    Bisoendial RJ, Kastelein JJ, Levels JH, et al.: Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 2005, 96:714–716.PubMedCrossRefGoogle Scholar
  17. 17.
    Crawford DC, Sanders CL, Qin X, et al.: Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation 2006, 114:2458–2465.PubMedCrossRefGoogle Scholar
  18. 18.
    Lange L, Carlson C, Hindorff L, et al.: Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 2006, 296:2703–2711.PubMedCrossRefGoogle Scholar
  19. 19.
    Ridker PM, Cannon CP, Morrow D, et al.: the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators: C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005, 352:20–28.PubMedCrossRefGoogle Scholar
  20. 20.
    Pepys MB, Hirschfield GM, Tennent GA, et al.: Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006, 440:1217–1221.PubMedCrossRefGoogle Scholar
  21. 21.
    Boerwinkle E, Ellsworth DL, Hallman DM, Biddinger A: Genetic analysis of atherosclerosis: a research paradigm for the common chronic diseases. Hum Mol Genet 1996, 5(Spec No):1405–1410.PubMedGoogle Scholar
  22. 22.
    Frohlich J, Dobiasova M, Lear S, Lee KW: The role of risk factors in the development of atherosclerosis. Crit Rev Clin Lab Sci 2001, 38:401–440.PubMedCrossRefGoogle Scholar
  23. 23.
    Pankow JS, Folsom AR, Cushman M, et al.: Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 2001, 154:681–689.PubMedCrossRefGoogle Scholar
  24. 24.
    Vickers MA, Green FR, Terry C, et al.: Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res 2002, 53:1029–1034.PubMedCrossRefGoogle Scholar
  25. 25.
    Retterstol L, Eikvar L, Berg K: A twin study of C-reactive protein compared to other risk factors for coronary heart disease. Atherosclerosis 2003, 169:279–282.PubMedCrossRefGoogle Scholar
  26. 26.
    MacGregor AJ, Gallimore JR, Spector TD, Pepys MB: Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins. Clin Chem 2004, 50:130–134.PubMedCrossRefGoogle Scholar
  27. 27.
    Province MA, Rao DC: General purpose model and a computer program for combined segregation and path analysis (SEGPATH): automatically creating computer programs from symbolic language model specifications. Genet Epidemiol 1995, 12:203–219.PubMedCrossRefGoogle Scholar
  28. 28.
    Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998, 62:1198–1211.PubMedCrossRefGoogle Scholar
  29. 29.
    Austin MA, Zhang C, Humphries SE, et al.: Heritability of C-reactive protein and association with apolipoprotein E genotypes in Japanese Americans. Ann Hum Genet 2004, 68(Pt 3):179–188.PubMedCrossRefGoogle Scholar
  30. 30.
    Kathiresan S, Larson MG, Vasan RS, et al.: Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 2006, 113:1415–1423.PubMedCrossRefGoogle Scholar
  31. 31.
    Carlson CS, Aldred SF, Lee PK, et al.: Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 2005, 77:64–77.PubMedCrossRefGoogle Scholar
  32. 32.
    Miller DT, Zee RY, Suk Danik J, et al.: Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 2005, 69(Pt 6):623–638.PubMedCrossRefGoogle Scholar
  33. 33.
    Dunning AM, Durocher F, Healey CS, et al.: The extent of linkage disequilibrium in four populations with distinct demographic histories. Am J Hum Genet 2000, 67:1544–1554.PubMedCrossRefGoogle Scholar
  34. 34.
    Reich DE, Cargill M, Bolk S, et al.: Linkage disequilibrium in the human genome. Nature 2001, 411:199–204.PubMedCrossRefGoogle Scholar
  35. 35.
    Reich DE, Schaffner SF, Daly MJ, et al.: Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet 2002, 32:135–142.PubMedCrossRefGoogle Scholar
  36. 36.
    Li SP, Liu TY, Goldman ND: cis-acting elements responsible for interleukin-6 inducible C-reactive protein gene expression. J Biol Chem 1990, 265:4136–4142.PubMedGoogle Scholar
  37. 37.
    Russell AI, Cunninghame Graham DS, Shepherd C, et al.: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet 2004, 13:137–147.PubMedCrossRefGoogle Scholar
  38. 38.
    Szalai AJ, Wu J, Lange EM, et al.: Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. J Mol Med 2005, 83:440–447.PubMedCrossRefGoogle Scholar
  39. 39.
    Brull DJ, Serrano N, Zito F, et al.: Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 2003, 23:2063–2069.PubMedCrossRefGoogle Scholar
  40. 40.
    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, 162:217–219.PubMedCrossRefGoogle Scholar
  41. 41.
    D’Aiuto F, Casas JP, Shah T, et al.: C-reactive protein (+1444C>T) polymorphism influences CRP response following a moderate inflammatory stimulus. Atherosclerosis 2005, 179:413–417.PubMedCrossRefGoogle Scholar
  42. 42.
    Kovacs A, Green F, Hansson LO, et al.: A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis 2005, 178:193–198.PubMedCrossRefGoogle Scholar
  43. 43.
    Suk HJ, Ridker PM, Cook NR, Zee RY: Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 2005, 178:139–145.PubMedCrossRefGoogle Scholar
  44. 44.
    Szalai AJ, McCrory MA, Cooper GS, et al.: Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene. Genes Immun 2002, 3:14–19.PubMedCrossRefGoogle Scholar
  45. 45.
    Szalai AJ, Alarcon GS, Calvo-Alen J, et al.: Systemic lupus erythematosus in a multiethnic US Cohort (LUMINA). XXX: association between C-reactive protein (CRP) gene polymorphisms and vascular events. Rheumatology (Oxford) 2005, 44:864–868.CrossRefGoogle Scholar
  46. 46.
    Obisesan TO, Leeuwenburgh C, Phillips T, et al.: C-reactive protein genotypes affect baseline, but not exercise training-induced changes, in C-reactive protein levels. Arterioscler Thromb Vasc Biol 2004, 24:1874–1879.PubMedCrossRefGoogle Scholar
  47. 47.
    Eklund C, Lehtimaki T, Hurme M: Epistatic effect of C-reactive protein (CRP) single nucleotide polymorphism (SNP) +1059 and interleukin-1B SNP +3954 on CRP concentration in healthy male blood donors. Int J Immunogenet 2005, 32:229–232.PubMedCrossRefGoogle Scholar
  48. 48.
    Cao H, Hegele RA: Human C-reactive protein (CRP) 1059G/C polymorphism. J Hum Genet 2000, 45:100–101.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen J, Zhao J, Huang J, et al.: −717A>G polymorphism of human C-reactive protein gene associated with coronary heart disease in ethnic Han Chinese: the Beijing atherosclerosis study. J Mol Med 2005, 83:72–78.PubMedCrossRefGoogle Scholar
  50. 50.
    Kardys I, de Maat MP, Uitterlinden AG, et al.: C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam Study. Eur Heart J 2006, 27:1331–1337.PubMedCrossRefGoogle Scholar
  51. 51.
    Cannon CP, Braunwald E, McCabe CH, et al.: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004, 350:1495–1504.PubMedCrossRefGoogle Scholar
  52. 52.
    Suk Danik J, Chasman DI, Cannon CP, et al.: Influence of genetic variation in the C-reactive protein gene on the inflammatory response during and after acute coronary ischemia. Ann Hum Genet 2006, 70(Pt 6):705–716.PubMedCrossRefGoogle Scholar
  53. 53.
    Verschuur M, van der Beek MT, Tak HS, et al.: Interindividual variation in the response by fibrinogen, C-reactive protein and interleukin-6 to yellow fever vaccination. Blood Coagul Fibrinolysis 2004, 15:399–404.PubMedCrossRefGoogle Scholar
  54. 54.
    Brull DJ, Montgomery HE, Sanders J, et al.: Interleukin-6 gene −174g>c and −572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 2001, 21:1458–1463.PubMedGoogle Scholar
  55. 55.
    Ferrari SL, Ahn-Luong L, Garnero P, et al.: Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 2003, 88:255–259.PubMedCrossRefGoogle Scholar
  56. 56.
    Kelberman D, Hawe E, Luong LA, et al.: Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe. The HIFMECH Study. Thromb Haemost 2004, 92:1122–1128.PubMedGoogle Scholar
  57. 57.
    Ganter U, Arcone R, Toniatti C, et al.: Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. Embo J 1989, 8:3773–3779.PubMedGoogle Scholar
  58. 58.
    Berger P, McConnell JP, Nunn M, et al.: C-reactive protein levels are influenced by common IL-1 gene variations. Cytokine 2002, 17:171–174.PubMedCrossRefGoogle Scholar
  59. 59.
    Eklund C, Jahan F, Pessi T, et al.: Interleukin 1B gene polymorphism is associated with baseline C-reactive protein levels in healthy individuals. Eur Cytokine Netw 2003, 14:168–171.PubMedGoogle Scholar
  60. 60.
    Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105:1135–1143.PubMedCrossRefGoogle Scholar
  61. 61.
    Vatay A, Bene L, Kovacs A, et al.: Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease. Immunogenetics 2003, 55:247–252.PubMedCrossRefGoogle Scholar
  62. 62.
    Araujo F, Pereira AC, Mota GF, et al.: The influence of tumor necrosis factor −308 and C-reactive protein G1059C gene variants on serum concentration of C-reactive protein: evidence for an age-dependent association. Clin Chim Acta 2004, 349(1–2):129–134.PubMedCrossRefGoogle Scholar
  63. 63.
    Papafili A, Hill MR, Brull DJ, et al.: Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 2002, 22:1631–1636.PubMedCrossRefGoogle Scholar
  64. 64.
    Cipollone F, Toniato E, Martinotti S, et al.: A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 2004, 291:2221–2228.PubMedCrossRefGoogle Scholar
  65. 65.
    Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, et al.: Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002, 347:185–192.PubMedCrossRefGoogle Scholar
  66. 66.
    Manttari M, Manninen V, Palosuo T, Ehnholm C: Apolipoprotein E polymorphism and C-reactive protein in dyslipidemic middle-aged men. Atherosclerosis 2001, 156:237–238.PubMedCrossRefGoogle Scholar
  67. 67.
    Kahri J, Soro-Paavonen A, Ehnholm C, Taskinen MR: ApoE polymorphism is associated with C-reactive protein in low-HDL family members and in normolipidemic subjects. Mediators Inflamm 2006, 2006:12587.PubMedCrossRefGoogle Scholar
  68. 68.
    Hingorani A, Humphries S: Nature’s randomised trials. Lancet 2005, 366:1906–1908.PubMedCrossRefGoogle Scholar
  69. 69.
    Davey Smith G, Lawlor DA, Harbord R, et al.: Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol 2005, 25:1051–1056.PubMedCrossRefGoogle Scholar
  70. 70.
    Timpson NJ, Lawlor DA, Harbord RM, et al.: C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 2005, 366:1954–1959.PubMedCrossRefGoogle Scholar
  71. 71.
    Glynn RJ: Commentary: Genes as instruments for evaluation of markers and causes. Int J Epidemiol 2006, 35:932–934.PubMedCrossRefGoogle Scholar
  72. 72.
    Casas JP, Shah T, Cooper J, et al.: Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 2006, 35:922–931.PubMedCrossRefGoogle Scholar
  73. 73.
    Wolford JK, Gruber JD, Ossowski VM, et al.: A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians. Mol Genet Metab 2003, 78:136–144.PubMedCrossRefGoogle Scholar
  74. 74.
    Balistreri CR, Vasto S, Listi F, et al.: Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study. Ann N Y Acad Sci 2006, 1067:276–281.PubMedCrossRefGoogle Scholar
  75. 75.
    Morita A, Nakayama T, Soma M: Association study between C-reactive protein genes and ischemic stroke in Japanese subjects. Am J Hypertens 2006, 19:593–600.PubMedCrossRefGoogle Scholar
  76. 76.
    Ortlepp JR, Graf J, Vesper K, et al.: Relationship of five inflammatory gene polymorphisms with morbidity and mortality in 533 patients admitted to an ICU. Inflammation 2005, 29:1–7.CrossRefGoogle Scholar
  77. 77.
    Davey Smith G, Ebrahim S: ’Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003, 32:1–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Lonn E, Yusuf S, Arnold MJ, et al.: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006, 354:1567–1577.PubMedCrossRefGoogle Scholar

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© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Center for Cardiovascular Disease PreventionBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

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