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The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk

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Abstract

Interest in C-reactive protein (CRP) and the association of its serum level in apparently healthy individuals to their cardiovascular disease risk has soared over the past decade. Recent studies have shown that the interindividual variations in CRP levels not only reflect environmental cues but are also a consequence of the genetic variation in the CRP gene itself. The importance of the relationship of CRP gene variants to CRP serum level and cardiovascular disease risk is important to establish CRP gene profiling as a clinical risk prediction tool and also to help test the cause-effect relationship between CRP and vascular disease. This article reviews recent studies that address the relationship of CRP gene polymorphisms to inflammation and cardiovascular risk.

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References and Recommended Reading

  1. Pepys MB, Baltz ML: Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Advances Immunol 1983, 34:141–212.

    Article  CAS  Google Scholar 

  2. Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med 1999, 340:115–126.

    Article  PubMed  CAS  Google Scholar 

  3. Ridker PM, Cushman M, Stampfer MJ, et al.: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997, 336:973–979.

    Article  PubMed  CAS  Google Scholar 

  4. de Ferranti SD, Rifai N: C-reactive protein: a nontraditional serum marker of cardiovascular risk. Cardiovasc Pathol 2007, 16:14–21.

    Article  PubMed  Google Scholar 

  5. Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007, 49:2129–2138.

    Article  PubMed  CAS  Google Scholar 

  6. Predicting heart attacks. The New York Times. November 17, 2002:A10.

  7. Hage FG, Szalai AJ: C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol 2007, 50:1115–1122.

    Article  PubMed  CAS  Google Scholar 

  8. Danik JS, Ridker PM: Genetic determinants of C-reactive protein. Curr Atheroscler Rep 2007, 9:195–203.

    Article  PubMed  CAS  Google Scholar 

  9. Venugopal SK, Devaraj S, Jialal I: Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role. Curr Opin Nephrol Hypertens 2005, 14:33–37.

    Article  PubMed  CAS  Google Scholar 

  10. Xing D, Hage FG, Chen YF, et al.: Exaggerated neointima formation in human C-reactive protein transgenic mice is IgG Fc receptor type I (Fc gamma RI)-dependent. Am J Pathol 2008, 172:22–30.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. Paul A, Ko KW, Li L, et al.: C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004, 109:647–655.

    Article  PubMed  CAS  Google Scholar 

  13. Teoh H, Quan A, Lovren F, et al.: Impaired endothelial function in C-reactive protein overexpressing mice. Atherosclerosis 2008 (in press).

  14. Hage FG, Xing D, Chen YF, et al.: Treatment with a human C-reactive protein specific antisense oligonucleotide reduces neointima formation in human C-reactive protein transgenic mice. J Clin Hypertens 2008, 10:A2.

    Article  Google Scholar 

  15. Kushner I, Rzewnicki D, Samols D: What does minor elevation of C-reactive protein signify? Am J Med 2006, 119:e117–128.

    Article  Google Scholar 

  16. Patel DN, King CA, Bailey SR, et al.: Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 2007, 282:27229–27238.

    Article  PubMed  CAS  Google Scholar 

  17. Ramji DP, Vitelli A, Tronche F, et al.: The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms. Nucleic Acid Res 1993, 21:289–294.

    Article  PubMed  CAS  Google Scholar 

  18. Toniatti C, Demartis A, Monaci P, et al.: Synergistic trans-activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites. EMBO J 1990, 9:4467–4475.

    PubMed  CAS  Google Scholar 

  19. Zhang D, Sun M, Samols D, Kushner I: STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. J Biol Chem 1996, 271:9503–9509.

    Article  PubMed  CAS  Google Scholar 

  20. Voleti B, Agrawal A: Regulation of basal and induced expression of C-reactive protein through an overlapping element for OCT-1 and NF-kappaB on the proximal promoter. J Immunol 2005, 175:3386–3390.

    PubMed  CAS  Google Scholar 

  21. 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 (Berlin, Germany) 2005, 83:440–447.

    CAS  Google Scholar 

  22. Shih PB, Manzi S, Shaw P, et al.: Genetic variation in Creactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations. J Rheum 2008 (in press).

  23. Edberg JC, Wu J, Langefeld CD, et al.: Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum Mol Genet 2008, 17:1147–1155.

    Article  PubMed  CAS  Google Scholar 

  24. Rhodes B, Wong A, Navarra SV, et al.: Genetic determinants of basal C-reactive protein expression in Filipino systemic lupus erythematosus families. Gene Immun 2008, 9:153–160.

    Article  CAS  Google Scholar 

  25. Jonsen A, Gunnarsson I, Gullstrand B, et al.: Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes. Rheumatology (Oxford) 2007, 46:1417–1421.

    Article  CAS  Google Scholar 

  26. Rhodes B, Meek J, Whittaker JC, Vyse TJ: Quantification of the Genetic Component of Basal C-Reactive Protein Expression in SLE Nuclear Families. Ann Hum Genet 2008 (in press).

  27. Bos SD, Suchiman HE, Kloppenburg M, et al.: Allelic variation at the C-reactive protein gene associates to both hand osteoarthritis severity and serum high sensitive C-reactive protein levels in the GARP study. Ann Rheum Dis 2008, 67:877–879.

    Article  PubMed  CAS  Google Scholar 

  28. Kivimaki M, Lawlor DA, Smith GD, et al.: Variants in the CRP gene as a measure of lifelong differences in average Creactive protein levels: the Cardiovascular Risk in Young Finns Study, 1980–2001. Am J Epidemiol 2007, 166:760–764.

    Article  PubMed  Google Scholar 

  29. Gimeno D, Ferrie JE, Elovainio M, et al.: When do social inequalities in C-reactive protein start? A life course perspective from conception to adulthood in the Cardiovascular Risk in Young Finns Study. Int J Epidemiol 2008, 37:290–298.

    Article  PubMed  CAS  Google Scholar 

  30. Shen J, Arnett DK, Parnell LD, et al.: Association of common C-reactive protein (CRP) gene polymorphisms with baseline plasma CRP levels and fenofibrate response: the GOLDN study. Diabetes Care 2008, 31:910–915.

    Article  PubMed  CAS  Google Scholar 

  31. Kolz M, Koenig W, Muller M, et al.: DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study. Eur Heart J 2008, 29:1250–1258.

    Article  PubMed  CAS  Google Scholar 

  32. Kruger B, Boger CA, Schroppel B, et al.: No effect of C-reactive protein (CRP) haplotypes on CRP levels and post-transplant morbidity and mortality in renal transplantation. Transpl Int 2008, 21:452–458.

    Article  PubMed  Google Scholar 

  33. Reiner AP, Wurfel MM, Lange LA, et al.: Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation. Arterioscler Thromb Vasc Biol 2008, 28:1407–1412.

    Article  PubMed  CAS  Google Scholar 

  34. Walston JD, Fallin MD, Cushman M, et al.: IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. Human Genet 2007, 122:485–494.

    Article  CAS  Google Scholar 

  35. Paik JK, Kim OY, Koh SJ, et al.: Additive effect of interleukin-6 and C-reactive protein (CRP) single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors. Clin Chim Acta 2007, 380:68–74.

    Article  PubMed  CAS  Google Scholar 

  36. Wong LY, Leung RY, Ong KL, Cheung BM: Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension. J Hum Hypertens 2007, 21:875–882.

    Article  PubMed  CAS  Google Scholar 

  37. Enquobahrie DA, Rice K, Williams OD, et al.: IL1B genetic variation and plasma C-reactive protein level among young adults: The CARDIA study. Atherosclerosis 2008 (in press).

  38. Reiner AP, Barber MJ, Guan Y, et al.: Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet 2008, 82:1193–1201.

    Article  PubMed  CAS  Google Scholar 

  39. Lakoski SG, Li L, Langefeld CD, et al.: The association between innate immunity gene (IRAK1) and C-reactive protein in the Diabetes Heart Study. Exper Mol Pathol 2007, 82:280–283.

    Article  CAS  Google Scholar 

  40. Rizzello V, Liuzzo G, Giannuario GD, et al.: 1059G/C polymorphism within the exon 2 of the C-reactive protein gene: relationship to C-reactive protein levels and prognosis in unstable angina. Coronary Artery Dis 2007, 18:533–538.

    Google Scholar 

  41. Ben-Assayag E, Shenhar-Tsarfaty S, Bova I, et al.: Triggered C-reactive protein (CRP) concentrations and the CRP gene - 717A>G polymorphism in acute stroke or transient ischemic attack. Eur J Neurol 2007, 14:315–320.

    Article  PubMed  CAS  Google Scholar 

  42. Benjamin EJ, Dupuis J, Larson MG, et al.: Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC Med Genet 2007, 8(Suppl 1):S11.

    Article  PubMed  Google Scholar 

  43. Melzer D, Perry JR, Hernandez D, et al.: A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 2008, 4:e1000072.

    Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Ruchat SM, Despres JP, Weisnagel SJ, et al.: Genomewide linkage analysis for circulating levels of adipokines and C-reactive protein in the Quebec family study (QFS). J Hum Genet 2008, 53:629–636.

    Article  PubMed  CAS  Google Scholar 

  47. Keenan HA, Poznik GD, Varo N, et al.: Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15. Atherosclerosis 2008, 196:863–870.

    Article  PubMed  CAS  Google Scholar 

  48. Ridker PM, Pare G, Parker A, et al.: Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study. Am J Hum Genet 2008, 82:1185–1192.

    Article  PubMed  CAS  Google Scholar 

  49. Lawlor DA, Harbord RM, Timpson NJ, et al.: The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants. PLoS ONE 2008, 3:e3011.

    Article  PubMed  Google Scholar 

  50. 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:e1395.

    Article  PubMed  Google Scholar 

  51. Gallicchio L, Chang H, Christo DK, et al.: Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland. Am J Epidemiol 2008, 167:807–813.

    Article  PubMed  Google Scholar 

  52. Hindorff LA, Rice KM, Lange LA, et al.: Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study. Atherosclerosis 2008, 197:922–930.

    Article  PubMed  CAS  Google Scholar 

  53. Reitz C, Berger K, de Maat MP, et al.: CRP gene haplotypes, serum CRP, and cerebral small-vessel disease: the Rotterdam Scan Study and the MEMO Study. Stroke 2007, 38:2356–2359.

    Article  PubMed  CAS  Google Scholar 

  54. Eklund C, Kivimaki M, Islam MS, et al.: C-reactive protein genetics is associated with carotid artery compliance in men in The Cardiovascular Risk in Young Finns Study. Atherosclerosis 2008, 196:841–848.

    Article  PubMed  CAS  Google Scholar 

  55. Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation. Eur J Epidemiol 2008, 23:531–540.

  56. Yan M, Zhao L, Zheng F, et al.: The relationship between gene polymorphism and CRP level in a Chinese Han population. Biochem Genet 2007, 45:1–9.

    Article  PubMed  CAS  Google Scholar 

  57. Sheu WH, Chen YD, Yu CY, et al.: C-reactive protein gene polymorphism 1009A>G is associated with serum CRP levels in Chinese men: a TCVGHAGE study. Clin Chim Acta 2007, 382:117–123.

    Article  PubMed  CAS  Google Scholar 

  58. 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 (Berlin) 2005, 83:72–78.

    CAS  Google Scholar 

  59. Rhodes B, Morris DL, Subrahmanyan L, et al.: Finemapping the genetic basis of CRP regulation in African Americans: a Bayesian approach. Hum Genet 2008, 123:633–642.

    Article  PubMed  CAS  Google Scholar 

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Hage, F.G., Szalai, A.J. The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk. Curr Atheroscler Rep 11, 124–130 (2009). https://doi.org/10.1007/s11883-009-0020-z

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