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Association of biomarkers of inflammation and HLA-DRB1 gene locus with risk of developing rheumatoid arthritis in females

  • Genes and Disease
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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation of the joints. Multiple factors, including HLA-DRB1 gene variants, influence the susceptibility to RA. The HLA-DRB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. In this study, we compared the inflammatory biomarkers values, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), between patients with RA and healthy control group of females of the Public Institution Health Centre of Sarajevo Canton. In addition, we estimated the frequencies of the HLA-DRB1 gene variants and their association with the risk for RA development in females. The haematological and biochemical tests were completed on automated analyzers. To assess the association between the HLA-DRB genes and the risk of RA in females, low-resolution genotyping of the HLA-DRB1, DRB3, DRB4, and DRB5 gene loci was performed by the sequence-specific polymerase chain reaction method (PCR-SSP). ESR and CRP were the most sensitive acute-phase reactants in females with RA and there was a correlation between ESR and CRP values in RA patients. There was significantly positive association between of the HLA-DRB1*03, *04, *08, *10, *11, and *14 variants and elevated values of ESR in RA patients, but negative between HLA-DRB1*03, *13 and *15 alleles and elevated CRP values. Furthermore, our results confirm genetic susceptibility to RA in a female population to the members of the HLA-DRB1*04 and *03 allelic groups, the DRB1*04/DRB1*04 and DRB1*03/DRB1*04 genotypes, and the DRB1*04-DRB4* or DRB1*03-DRB3* haplotypes, which, therefore, represent risk factors for the development of this disease. According to our results, the DRB1*01/DRB1*15 and DRB1*07/DRB1*16 genotypes and the HLA-DRB5 gene locus represent a protective factor for RA. The presence of specific HLA-DRB1 gene variants increases the risk of developing RA, while other variants provide protection against disease. Therefore, HLA typing could be helpful in the prediction of RA development and establishing and confirming a definitive diagnosis of autoimmune diseases in some subjects. A strong association with the higher levels of ESR and CRP could be used to establish definitive diagnosis and introduce of early treatment of RA to prevent the occurrence of RA symptoms.

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References

  1. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584

    Article  PubMed  Google Scholar 

  2. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K (2018) Rheumatoid arthritis. Nat Rev Dis Primer 4:18001. https://doi.org/10.1038/nrdp.2018.1

    Article  Google Scholar 

  3. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361. https://doi.org/10.1038/nature01661

    Article  CAS  PubMed  Google Scholar 

  4. Choy E (2012) Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology 51:v3–v11. https://doi.org/10.1093/rheumatology/kes113

    Article  CAS  PubMed  Google Scholar 

  5. Stastny P (1978) Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298(16):869–871. https://doi.org/10.1056/NEJM197804202981602

    Article  CAS  PubMed  Google Scholar 

  6. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30(11):1205–1213. https://doi.org/10.1002/art.1780301102

    Article  CAS  PubMed  Google Scholar 

  7. Viatte S, Plant D, Raychaudhuri S (2013) Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9(3):141–153. https://doi.org/10.1038/nrrheum.2012.237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 16(3):1215. https://doi.org/10.1093/nar/16.3.1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sokolovic S, Dervisevic V, Fisekovic S (2014) Mental health status can reflect disease activity in rheumatoid arthritis. Eur J Rheumatol 1:55–57. https://doi.org/10.5152/eurjrheumatol.2014.020

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kim KW, Kim BM, Moon HW, Lee SH, Kim HR (2015) Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Res Ther 17(1):41. https://doi.org/10.1186/s13075-015-0563-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nigrovic PA, Raychaudhuri S, Thompson SD (2018) Review: genetics and the classification of arthritis in adults and children. Arthritis Rheum 70(1):7–17. https://doi.org/10.1002/art.40350

    Article  Google Scholar 

  12. Fejzic E, Sahovic A, Sisic S, Alijagic A, Suljevic D (2017) Crosslinks between human leukocyte antigen DRB1*01 and human leukocyte antigen DRB1*13 allelic variants and occurrence of rheumatoid arthritis in patients from Federation of Bosnia and Herzegovina. Arch Rheumatol 32(4):290–297. https://doi.org/10.5606/ArchRheumatol.2017.6258

    Article  PubMed  PubMed Central  Google Scholar 

  13. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG, BIRAC Consortium, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AHM, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP, YEAR Consortium, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514. https://doi.org/10.1038/ng.582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. de Vries N, Rønningen KS, Tilanus MGJ, Bouwens-Rambouts A, Segal R, Egeland T, Thorsby E, van de Putte LB, Brautbar C (1993) HLA-DR1 and rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB1*0102 is the predominant HLA-DR1 subtype. Tissue Antigens 41(1):26–30. https://doi.org/10.1111/j.1399-0039.1993.tb01973.x

    Article  PubMed  Google Scholar 

  15. Cruz-Tapias P, Rojas-Villarraga A, Maier Moore S, Anaya JM (2012) HLA and Sjögren’s syndrome susceptibility A meta-analysis of worldwide studies. Autoimmun Rev 11(4):281–287. https://doi.org/10.1016/j.autrev.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  16. Shimane K, Kochi Y, Suzuki A, Okada Y, Ishii T, Horita T, Saito K, Okamoto A, Nishimoto N, Myouzen K, Kubo M, Hirakata M, Sumida T, Takasaki Y, Yamada R, Nakamura Y, Kamatani N, Yamamoto K (2013) An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes. Rheumatology 52(7):1172–1182. https://doi.org/10.1093/rheumatology/kes427

    Article  CAS  PubMed  Google Scholar 

  17. Tuokko J, Nejentsev S, Luukkainen R, Toivanen A, Ilonen J (2001) HLA haplotype analysis in Finnish patients with rheumatoid arthritis. Arthritis Rheum 44(2):315–322. https://doi.org/10.1002/1529-0131(200102)44:2%3c315:AID-ANR48%3e3.0.CO;2-G

    Article  CAS  PubMed  Google Scholar 

  18. Van Jaarsveld CHM, Otten HG, Jacobs JWG, Kruize AA, Brus HLM, Bijlsma JWJ (1998) Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing. Br J Rheumatol 37(4):411–416. https://doi.org/10.1093/rheumatology/37.4.411

    Article  PubMed  Google Scholar 

  19. Stark K, Rovenský J, Blažičková S, Grosse-Wilde H, Ferencik S, Hengstenberg C, Straub RH (2009) Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls. Arthritis Res Ther 11(3):R70. https://doi.org/10.1186/ar2699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Balsa A, Minaur NJ, Pascual-Salcedo D, McCabe C, Balas A, Fiddament B, Vicario JL, Cox NL, Martín-Mola E, Hall ND (2000) Class II MHC antigens in early rheumatoid arthritis in Bath (UK) and Madrid (Spain). Rheumatology 39(8):844–849. https://doi.org/10.1093/rheumatology/39.8.844

    Article  CAS  PubMed  Google Scholar 

  21. Kinikli G, Ateş A, Turgay M, Akay G, Kinikli S, Tokgöz G (2003) HLA-DRB1 genes and disease severity in rheumatoid arthritis in Turkey. Scand J Rheumatol 32(5):277–280. https://doi.org/10.1080/03009740310003901

    Article  CAS  PubMed  Google Scholar 

  22. Fathi NA, Ezz-Eldin AM, Mosad E, Bakry RM, Hamed HB, Ahmed S, Mahmoud M, Rashed HA, Abdullah F (2008) Diagnostic performance and predictive value of rheumatoid factor, anti-cyclic-citrullinated peptide antibodies and HLA-DRB1 locus genes in rheumatoid arthritis. Int Arch Med 1(1):20. https://doi.org/10.1186/1755-7682-1-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Del Rincón I, Escalante A (1999) HLA–DRB1 alleles associated with susceptibility or resistance to rheumatoid arthritis, articular deformities, and disability in Mexican Americans. Arthritis Rheum 42(7):1329–1338. https://doi.org/10.1002/1529-0131(199907)42:7%3c1329:AID-ANR5%3e3.0.CO;2-1

    Article  PubMed  Google Scholar 

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Funding

No funding was received for this study.

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Authors and Affiliations

  1. Department of Laboratory Diagnostics, The Public Institution Health Centre of Sarajevo Canton, Sarajevo, Bosnia and Herzegovina

    Biljana Klimenta

  2. Department of Biology, Faculty of Science, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

    Hilada Nefic

  3. Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina

    Nenad Prodanovic

  4. Department of Medical Biochemistry, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

    Radivoj Jadric

  5. Department of Biochemistry, Clinical University Centre of Tuzla, Tuzla, Bosnia and Herzegovina

    Fatima Hukic

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  1. Biljana Klimenta
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  2. Hilada Nefic
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  4. Radivoj Jadric
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  5. Fatima Hukic
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Contributions

All authors contributed to the design of the research and interpretation of the data, and critical revisions to the content. BK and HN contributed to data collection. HN analysed the data. The first draft of the manuscript was written by HN and all authors commented on the previous versions of the manuscript. All authors read and approved the final version of manuscript and take full responsibility for the accuracy or integrity of all parts of it. Writing review and editing: Springer Nature Research Editing Service.

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Correspondence to Hilada Nefic.

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Conflict of interest

Author Biljana Klimenta, author Hilada Nefic, author Nenad Prodanovic, author Radivoj Jadric, and author Fatima Hukic declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (the Research Ethics Committee of the Public Institution Health Centre of Sarajevo Canton, Bosnia and Herzegovina: 01-08-5080-2/16) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Klimenta, B., Nefic, H., Prodanovic, N. et al. Association of biomarkers of inflammation and HLA-DRB1 gene locus with risk of developing rheumatoid arthritis in females. Rheumatol Int 39, 2147–2157 (2019). https://doi.org/10.1007/s00296-019-04429-y

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  • DOI: https://doi.org/10.1007/s00296-019-04429-y

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