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Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene

Genes & Immunity volume 3, pages 14–19 (2002)Cite this article

Abstract

Elevation of baseline C-reactive protein (CRP) is associated with increased risk of cardiac disease. This increase might reflect low-grade inflammation, but differences in CRP serum levels might also have a genetic component. To test this possibility, we investigated whether a polymorphic GT-repeat in the intron of the CRP gene contributes to variation in baseline CRP. We found that the polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus, viz. donors carrying two GT16 alleles, two GT21alleles, or GT16/21 heterozygotes had two-fold lower serum CRP than those with other genotypes. The frequency of GT16 and GT21 was two-fold higher in Caucasians than in African-Americans, but there was no difference in allele distribution between patients and controls. It is not yet known how this genetic polymorphism mediates its effect on CRP expression, and it probably is not a systemic lupus erythematosus susceptibility factor. Rather, the CRP intron polymorphism likely modifies the disease phenotype. On the other hand, the fact that baseline CRP does have a genetic component suggests that in coronary disease, stratification of risk assessment based on CRP levels might be enhanced by consideration of this polymorphism.

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References

  1. Shrive AK, Cheetham GMT, Holden D et al. Three dimensional structure of human C-reactive protein Nat Struct Biol 1996 3: 346–354

    Article  CAS  Google Scholar 

  2. Volanakis JE, Kaplan MH . Specificity of C-reactive protein for choline phosphate residues of pneumococcal C-polysaccharide Proc Soc Exp Biol Med 1971 136: 612–614

    Article  CAS  Google Scholar 

  3. Agrawal A, Kilpatrick JM, Volanakis JE . Structure and function of human C-reactive protein. In: Mackiewicz A, Kushner I,Baumann H (eds) Acute Phase Proteins: Molecular Biology, Biochemistry, and Clinical Applications CRC Press: Ann Arbor MI 1993 pp 79–92

    Google Scholar 

  4. Volanakis JE, Xu Y, Macon KJ . Human C-reactive protein and host defense. In: Marchalonis JJ, Reinisch CL (eds) Defense Molecules Alan R Liss: New York 1990 pp 161–175

    Google Scholar 

  5. Kaplan MH, Volanakis JE . Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphinogomyelin J Immunol 1974 112: 2135–2147

    CAS  PubMed  Google Scholar 

  6. Marnell LL, Mold C, Volzer MA, Burlingame RW, DuClos TW . C-reactive protein binds to FcγRI in transfected COS cells J Immunol 1995 155: 2185–2193

    CAS  PubMed  Google Scholar 

  7. Stein M-P, Mold C, DuClos TW . C-reactive protein binding to murine leukocytes requires Fcγ receptors J Immunol 2000 164: 1514–1520

    Article  CAS  Google Scholar 

  8. Szalai AJ, Briles DE, Volanakis JE . Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice J Immunol 1995 155: 2557–2563

    CAS  Google Scholar 

  9. Szalai AJ, VanCott JL, McGhee JR, Volanakis JE, Benjamin WH Jr . Human C-reactive protein is protective against fatal Salmonella enterica Serovar Typhimurium infection in transgenic mice Infect Immun 2000 68: 5652–5656

    Article  CAS  Google Scholar 

  10. Gershov D, Kim S, Brot N, Elkon KB . C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity J Exp Med 2000 192: 1353–1363

    Article  CAS  Google Scholar 

  11. Rosen A, Casciola-Rosen L . Clearing the way to mechanisms of autoimmunity Nat Med 2001 7: 664–665

    Article  CAS  Google Scholar 

  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: 973–979

    Article  CAS  Google Scholar 

  13. Westhuyzen J, Healy H . Review: biology and relevance of C-reactive protein in cardiovascular and renal disease Ann Clin Lab Sci 2000 30: 133–143

    CAS  PubMed  Google Scholar 

  14. Ballou SP, Kushner I . C-reactive protein and the acute phase response Adv Intern Med 1992 37: 313–336

    CAS  PubMed  Google Scholar 

  15. Gabay C, Roux-Lombard P, de Moerloose P, Dayer J-M, Vischer T, Guerne P-A . Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis J Rheumatol 1993 20: 815–821

    CAS  PubMed  Google Scholar 

  16. Pepys MB, Lanham JG, DeBeer FC . C-reactive protein in SLE Clin Rheum Dis 1982 8: 91–103

    CAS  PubMed  Google Scholar 

  17. DuClos TW, Zlock LT, Rubin RL . Analysis of the binding of C-reactive protein to histones and chromatin J Immunol 1988 141: 4266–4270

    CAS  Google Scholar 

  18. Minota S, Morino N, Sakurai H, Yamada A, Yazaki Y . Interrelationship between autoepitope, DNA-binding domain, and CRP-binding domain on a histone H1 molecule Clin Immunol Immunopathol 1993 66: 269–271

    Article  CAS  Google Scholar 

  19. DuClos TW . C-reactive protein reacts with U1 small nuclear ribonucleoproteins J Immunol 1989 143: 2553–2559

    CAS  Google Scholar 

  20. Robey FA, Jones KD, Steinberg AD . C-reactive protein mediates the solubilization of nuclear DNA by complement in vitro J Exp Med 1985 161: 1344–1356

    Article  CAS  Google Scholar 

  21. DuClos TW, Zlock LT, Hicks PS, Mold C . Decreased autoantibody levels and enhanced survival of (NZB × NZW)F1 mice treated with C-reactive protein Clin Immunol Immunopathol 1994 70: 22–27

    Article  CAS  Google Scholar 

  22. Burlingame RW, Volzer MA, Harris J, DuClos TW . The effects of acute phase proteins on clearance of chromatin from the circulation of normal mice J Immunol 1996 156: 4783–4788

    CAS  PubMed  Google Scholar 

  23. Szalai AJ, Marion TN, Weaver CT, Volanakis JE . Human C-reactive protein (CRP) is protective against murine SLE in NZB/W F1 mice Clin Exp Rheumatol 1998 16: 201 (Abstr. 24)

    Google Scholar 

  24. Szalai AJ, van Ginkel FW, Dalrymple SA, Murray R, McGhee JR, Volanakis JE . Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice J Immunol 1998 160: 5294–5299

    CAS  PubMed  Google Scholar 

  25. Maire MA, Barnet B, Carpenter N, Miescher PA, Lambert P-H . Identification of components of IC purified from human sera. I. Immune complexes purified from sera of patients with SLE Clin Exp Immunol 1983 51: 215–224

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Shai R, Quismorio FP, Li L et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families Hum Mol Genet 1999 8: 639–644

    Article  CAS  Google Scholar 

  27. Moser KL, Gray-McGuire C, Kelly J et al. Genetic linkages to human systemic lupus erythematosus FASEB J 2000 14: A1210 (Abstr. 186.30)

    Google Scholar 

  28. Moser KL, Neas BR, Salmon JE et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees Proc Natl Acad Sci USA 1998 95: 14869–14874

    Article  CAS  Google Scholar 

  29. Walsh MT, Divane A, Whitehead AS . Fine mapping of the human pentraxin gene region on chromosome 1q23 Immunogenetics 1996 44: 62–69

    Article  CAS  Google Scholar 

  30. Lei K-J, Liu T, Zon G, Soravia E, Liu T-Y, Goldman ND . Genomic DNA sequence for human C-reactive protein J Biol Chem 1985 260: 13377–13383

    CAS  PubMed  Google Scholar 

  31. Woo P, Korenberg JR, Whitehead AS . Characterization of genomic and complementary DNA sequence of human C-reactive protein, and comparison with the complementary sequence of serum amyloid P component J Biol Chem 1985 260: 13384–13388

    CAS  PubMed  Google Scholar 

  32. Weber JL, Kwitek AE, May PE . Dinucleotide repeat polymorphism at the CRP locus Nucl Acid Res 1990 18: 4635

    Google Scholar 

  33. Pankow JS, Folsom AR, Cushman M et al. Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study Atheriosclerosis 2001 154: 681–689

    Article  CAS  Google Scholar 

  34. Margaglione M, Cappucci G, Colaizzo D, Vecchione G, Grandone E, Di Minno G . C-reactive protein in offspring is associated with the occurrence of myocardial infarction in first-degree relatives Arterioscler Thromb Vasc Biol 2000 20: 198–203

    Article  CAS  Google Scholar 

  35. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J . A Taq1 polymorphism in the human interleukin-1β (IL-1β) gene correlates with IL-1β secretion in vitro Eur J Clin Invest 1992 22: 396–402

    Article  CAS  Google Scholar 

  36. Pandey JP, Takeuchi F . TNF-α and TNF-β gene polymorphism in systemic sclerosis Human Immunol 1999 60: 1128–1130

    Article  CAS  Google Scholar 

  37. Pravica V, Perrey C, Stevens A, Lee J-H, Hutchinson IV . A single nucleotide polymorphism in the first intron of the IFN-γ gene: Absolute correlation with a polymorphic CA microsatellite marker of high INF-γ production Human Immunol 2000 61: 863–866

    Article  CAS  Google Scholar 

  38. Watson JD, Crick FHC . A structure for deoxyribose nucleic acid Nature 1953 171: 737–738

    Article  CAS  Google Scholar 

  39. Adler AJ, Scheller A, Robins DM . The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences Mol Cell Biol 1993 13: 6326–6335

    Article  CAS  Google Scholar 

  40. Kushner I . C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biological aging Cleve Clin J Med 2001 68: 535–537

    Article  CAS  Google Scholar 

  41. McCarty DJ, Manzi S, Mger TA Jr eds Ramsey-Goldman R, LaPorte RE, Kwoh CK . Incidence of systemic lupus erythematosus. Race and gender differences Arthritis Rheum 1995 38: 1260–1270

    Article  CAS  Google Scholar 

  42. Stein MP, Edberg JC, Kimberly RP et al. C-reactive protein binding to FcgammaRIIa on human monocytes and neutrophils is allele-specific J Clin Invest 2000 105: 369–376

    Article  CAS  Google Scholar 

  43. Salmon JE, Millard S, Schachter LA et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans J Clin Invest 1996 97: 1348–1354

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    A J Szalai, M A McCrory, J Wu & R P Kimberly

  2. Epidemiology Branch, NIEHS, Research Triangle Park, NC 27709, USA

    G S Cooper

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  1. A J Szalai
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  2. M A McCrory
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  3. G S Cooper
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  4. J Wu
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  5. R P Kimberly
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Corresponding author

Correspondence to A J Szalai.

Additional information

This work was supported by: the intramural research program of the National Institute of Environmental Health Sciences and National Center for Minority Health and Health Disparities of the NIH (GSC), NIH Grant R29 AI42183 (AJS), and the Specialized Center of Research in Genetics of SLE P50 AR45231 (RPK).

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Szalai, A., McCrory, M., Cooper, G. 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 3, 14–19 (2002). https://doi.org/10.1038/sj.gene.6363820

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  • DOI: https://doi.org/10.1038/sj.gene.6363820

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