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The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis

Genes & Immunity volume 16, pages 446–451 (2015)Cite this article

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Abstract

This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25–75) disease duration of 1 (0.6–1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25–75) disease duration of 8.9 (3.5–17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19–0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15–1.95) mg dl−1 when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.

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References

  1. McInnes IB, Schett G . The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205–2219.

    Article  CAS  Google Scholar 

  2. Walters MT, Stevenson FK, Goswami R, Smith JL, Cawley MI . Comparison of serum and synovial fluid concentrations of beta 2-microglobulin and C reactive protein in relation to clinical disease activity and synovial inflammation in rheumatoid arthritis. Ann Rheum Dis 1989; 48: 905–911.

    Article  CAS  Google Scholar 

  3. Zeller JM, Kubak BM, Gewurz H . Binding sites for C-reactive protein on human monocytes are distinct from IgG Fc receptors. Immunology 1989; 67: 51–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Potempa LA, Zeller JM, Fiedel BA, Kinoshita CM, Gewurz H . Stimulation of human neutrophils, monocytes, and platelets by modified C-reactive protein (CRP) expressing a neoantigenic specificity. Inflammation 1988; 12: 391–405.

    Article  CAS  Google Scholar 

  5. James K, Baum LL, Vetter ML, Gewurz H . Interactions of C-reactive protein with lymphoid cells. Ann N Y Acad Sci 1982; 389: 274–285.

    Article  CAS  Google Scholar 

  6. Mallya RK, Vergani D, Tee DE, Bevis L, de Beer FC, Berry H et al. Correlation in rheumatoid arthritis of concentrations of plasma C3d, serum rheumatoid factor, immune complexes and C-reactive protein with each other and with clinical features of disease activity. Clin Exp Immunol 1982; 48: 747–753.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N . Comparison of Disease Activity Score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values. Ann Rheum Dis 2007; 66: 407–409.

    Article  CAS  Google Scholar 

  8. Ranganath VK, Khanna D, Paulus HE . ACR remission criteria and response criteria. Clin Exp Rheumatol 2006; 24 (6 Suppl 43): S-14–S-21.

    Google Scholar 

  9. Wolfe F, Pincus T . The level of inflammation in rheumatoid arthritis is determined early and remains stable over the longterm course of the illness. J Rheumatol 2001; 28: 1817–1824.

    CAS  PubMed  Google Scholar 

  10. 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: 2458–2465.

    Article  CAS  Google Scholar 

  11. Szalai AJ, Wu J, Lange EM, McCrory MA, Langefeld CD, Williams A 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.

    Article  CAS  Google Scholar 

  12. 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: 2703–2711.

    Article  CAS  Google Scholar 

  13. Rhodes B, Merriman ME, Harrison A, Nissen MJ, Smith M, Stamp L et al. A genetic association study of serum acute-phase C-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation. PLoS Med 2010; 7: e1000341.

    Article  Google Scholar 

  14. Hung AM, Crawford DC, Griffin MR, Brown-Gentry K, Lipkowitz MS, Siew ED et al. CRP polymorphisms and progression of chronic kidney disease in African Americans. Clin J Am Soc Nephrol 2010; 5: 24–33.

    Article  CAS  Google Scholar 

  15. Kuhlenbaeumer G, Huge A, Berger K, Kessler C, Voelzke H, Funke H et al. Genetic variants in the C-reactive protein gene are associated with microangiopathic ischemic stroke. Cerebrovasc Dis 2010; 30: 476–482.

    Article  CAS  Google Scholar 

  16. Kok EH, Alanne-Kinnunen M, Isotalo K, Luoto T, Haikonen S, Goebeler S et al. CRP gene variation affects early development of Alzheimer's disease-related plaques. J Neuroinflammation 2011; 8: 96.

    Article  CAS  Google Scholar 

  17. Yang SH, Huang CJ, Chang SC, Lin JK . Association of C-reactive protein gene polymorphisms and colorectal cancer. Ann Surg Oncol 2011; 18: 1907–1915.

    Article  Google Scholar 

  18. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M 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.

    Article  CAS  Google Scholar 

  19. Machold KP, Stamm TA, Nell VP, Pflugbeil S, Aletaha D, Steiner G et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology (Oxford) 2007; 46: 342–349.

    Article  CAS  Google Scholar 

  20. Bridges SL Jr ., Causey ZL, Burgos PI, Huynh BQ, Hughes LB, Danila MI et al. Radiographic severity of rheumatoid arthritis in African Americans: results from a multicenter observational study. Arthritis Care Res (Hoboken) 2010; 62: 624–631.

    Article  Google Scholar 

  21. Tamhane A, Redden DT, McGwin G Jr ., Brown EE, Westfall AO, RJ Reynolds 4th et al. Comparison of the disease activity score using erythrocyte sedimentation rate and C-reactive protein in African Americans with rheumatoid arthritis. J Rheumatol 2013; 40: 1812–1822.

    Article  CAS  Google Scholar 

  22. Plant D, Ibrahim I, Lunt M, Eyre S, Flynn E, Hyrich KL et al. Correlation of C-reactive protein haplotypes with serum C-reactive protein level and response to anti-tumor necrosis factor therapy in UK rheumatoid arthritis patients: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort. Arthritis Res Ther 2012; 14: R214.

    Article  CAS  Google Scholar 

  23. Syversen SW, Gaarder PI, Goll GL, Odegard S, Haavardsholm EA, Mowinckel P et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis 2008; 67: 212–217.

    Article  CAS  Google Scholar 

  24. Vastesaeger N, Xu S, Aletaha D St, Clair EW, Smolen JS . A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford) 2009; 48: 1114–1121.

    Article  CAS  Google Scholar 

  25. Knevel R, Grondal G, Huizinga TW, Visser AW, Jonsson H, Vikingsson A et al. Genetic predisposition of the severity of joint destruction in rheumatoid arthritis: a population-based study. Ann Rheum Dis 2012; 71: 707–709.

    Article  Google Scholar 

  26. Cox A, Camp NJ, Cannings C, di Giovine FS, Dale M, Worthington J et al. Combined sib-TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis. Hum Mol Genet 1999; 8: 1707–1713.

    Article  CAS  Google Scholar 

  27. Khanna D, Wu H, Park G, Gersuk V, Gold RH, Nepom GT et al. Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort. Arthritis Rheum 2006; 54: 1105–1116.

    Article  CAS  Google Scholar 

  28. Reneses S, Gonzalez-Escribano MF, Fernandez-Suarez A, Pestana L, Davila B, Wichmann I et al. The value of HLA-DRB1 shared epitope, -308 tumor necrosis factor-alpha gene promoter polymorphism, rheumatoid factor, anti-citrullinated peptide antibodies, and early erosions for predicting radiological outcome in recent-onset rheumatoid arthritis. J Rheumatol 2009; 36: 1143–1149.

    Article  CAS  Google Scholar 

  29. Prots I, Skapenko A, Wendler J, Mattyasovszky S, Yone CL, Spriewald B et al. Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis. Arthritis Rheum 2006; 54: 1491–1500.

    Article  CAS  Google Scholar 

  30. Burgos PI, Causey ZL, Tamhane A, Kelley JM, Brown EE, Hughes LB et al. Association of IL4R single-nucleotide polymorphisms with rheumatoid nodules in African Americans with rheumatoid arthritis. Arthritis Res Ther 2010; 12: R75.

    Article  Google Scholar 

  31. Scherer HU, van der Linden MP, Kurreeman FA, Stoeken-Rijsbergen G, Cessie S, Huizinga TW et al. Association of the 6q23 region with the rate of joint destruction in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 567–570.

    Article  Google Scholar 

  32. Knevel R, de Rooy DP, Gregersen PK, Lindqvist E, Wilson AG, Grondal G et al. Studying associations between variants in TRAF1-C5 and TNFAIP3-OLIG3 and the progression of joint destruction in rheumatoid arthritis in multiple cohorts. Ann Rheum Dis 2012; 71: 1753–1755.

    Article  CAS  Google Scholar 

  33. Lard LR, van Gaalen FA, Schonkeren JJ, Pieterman EJ, Stoeken G, Vos K et al. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. Arthritis Rheum 2003; 48: 1841–1848.

    Article  CAS  Google Scholar 

  34. van der Linden MP, Feitsma AL, le Cessie S, Kern M, Olsson LM, Raychaudhuri S et al. Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis. Arthritis Rheum 2009; 60: 2242–2247.

    Article  CAS  Google Scholar 

  35. Marinou I, Healy J, Mewar D, Moore DJ, Dickson MC, Binks MH et al. Association of interleukin-6 and interleukin-10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody status. Arthritis Rheum 2007; 56: 2549–2556.

    Article  CAS  Google Scholar 

  36. Nemec P, Pavkova-Goldbergova M, Gatterova J, Vasku A, Soucek M . Association of the 5 A/6 A promoter polymorphism of the MMP-3 gene with the radiographic progression of rheumatoid arthritis. Ann N Y Acad Sci 2007; 1110: 166–176.

    Article  CAS  Google Scholar 

  37. Furuya T, Hakoda M, Ichikawa N, Higami K, Nanke Y, Yago T et al. Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity phenotypes in Japanese patients with early rheumatoid arthritis. Clin Rheumatol 2007; 26: 2137–2141.

    Article  Google Scholar 

  38. van Zeben D, Hazes JM, Zwinderman AH, Cats A, Schreuder GM, D'Amaro J et al. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study. Arthritis Rheum 1991; 34: 822–830.

    Article  CAS  Google Scholar 

  39. Reveille JD, Alarcon GS, Fowler SE, Pillemer SR, Neuner R, Clegg DO et al. HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis. Arthritis Rheum 1996; 39: 1802–1807.

    Article  CAS  Google Scholar 

  40. Wagner U, Kaltenhauser S, Sauer H, Arnold S, Seidel W, Hantzschel H et al. HLA markers and prediction of clinical course and outcome in rheumatoid arthritis. Arthritis Rheum 1997; 40: 341–351.

    Article  CAS  Google Scholar 

  41. Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK, Westfall AO et al. The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 2008; 58: 349–358.

    Article  Google Scholar 

  42. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

    Article  CAS  Google Scholar 

  43. van der Heijde D . How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000; 27: 261–263.

    CAS  PubMed  Google Scholar 

  44. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, 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: 499–511.

    Article  Google Scholar 

  45. Mikuls TR, Holers VM, Parrish L, Kuhn KA, Conn DL, Gilkeson G et al. Anti-cyclic citrullinated peptide antibody and rheumatoid factor isotypes in African Americans with early rheumatoid arthritis. Arthritis Rheum 2006; 54: 3057–3059.

    Article  Google Scholar 

  46. Aziz N, Fahey JL, Detels R, Butch AW . Analytical performance of a highly sensitive C-reactive protein-based immunoassay and the effects of laboratory variables on levels of protein in blood. Clin Diagn Lab Immunol 2003; 10: 652–657.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rhodes B, Morris DL, Subrahmanyan L, Aubin C, de Leon CF, Kelly JF et al. Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach. Hum Genet 2008; 123: 633–642.

    Article  CAS  Google Scholar 

  48. Edberg JC, Wu J, Langefeld CD, Brown EE, Marion MC, McGwin G Jr . et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum Mol Genet 2008; 17: 1147–1155.

    Article  CAS  Google Scholar 

  49. Ronaghi M, Uhlen M, Nyren P . A sequencing method based on real-time pyrophosphate. Science 1998; 281 (5375): 363–365.

    Article  CAS  Google Scholar 

  50. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  51. Hosmer DW, Lemeshow S . Applied Logistic Regression. Wiley: New York, NY, USA, 2000.

    Book  Google Scholar 

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Acknowledgements

The work reported in the manuscript was supported by the UAB Center for Clinical and Translational Studies (grant number 5UL1 RR025777-03 from the NIH National Center for Research Resources; NIH N01 AR-6-2278—Continuation of the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry); NIH 2P60 AR048095-06 Multidisciplinary Clinical Research Center Project 3: Predictors of Rheumatoid Arthritis Severity in African Americans (SLB); and NIH K23 AR62100 (MID), NIH K01 AR060848 (RJR) and an American College of Rheumatology Research and Education Foundation Within Our Reach Rheumatoid Arthritis Translational Research Grant (SLB). The study sponsors were not involved in the study design, the collection, analysis and interpretation data, the writing of the report or in the decision to submit the paper for publication. We acknowledge the contribution of the following CLEAR Investigators: Beth L Jonas, MD, University of North Carolina, Chapel Hill, NC, USA; Edwin A Smith, MD, Medical University of South Carolina, Charleston, SC, USA; Richard D Brasington, Jr, MD, Washington University, St. Louis, MO, USA for providing access to data for this study. We thank Peter K Gregersen, MD at The Feinstein Institute for Medical Research, Manhasset, NY, USA, for providing access to previous immunochip genotyping data for this study.

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Authors and Affiliations

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

    M I Danila, K Raman, L Chen, R J Reynolds, L B Hughes, A J Szalai & S L Bridges Jr

  2. Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    A O Westfall, D K Arnett & G McGwin

  3. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    D M van der Heijde

  4. Department of Medicine, Emory University, Atlanta, GA, USA

    D Conn

  5. Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

    L F Callahan

  6. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    L W Moreland

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  1. M I Danila
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Correspondence to M I Danila.

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DM van der Heijde is Director of Imaging Rheumatology BV, The Netherlands. The remaining authors declare no conflict of interest.

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Danila, M., Westfall, A., Raman, K. et al. The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis. Genes Immun 16, 446–451 (2015). https://doi.org/10.1038/gene.2015.24

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