Association of HLA-B27 Gene and Rheumatoid Arthritis: Analysis of Potential Role as a Predictive Biomarker
Rheumatoid arthritis (RA) is a predominant inflammatory arthritis in human. The function of HLA-B27 gene in other types of arthritis has been studied, however, its function in RA is unclear. This study investigated the relative expression of HLA-B27 gene in RA patients compared to normal control and assesses its suitability as a biomarker for early detection of RA. Bioinformatics analysis was used to determine the profile of HLA-B27 gene in different human tumors to demonstrate the possible involvement of HLA-B27 in both RA and cancer; and also, to discover its functional association with other human genes. Samples of human blood from RA patients and healthy individuals were collected, and RNA extraction, cDNA synthesis and qPCR were carried out to detect relative expression of HLA-B27. ROC analysis was undertaken to investigate HLA-B27 diagnostic performance; GENT2 platform was used to compare HLA-B27 expression levels in different human tumors, and gene-gene interaction network was generated using GeneMANIA to identify correlation of HLA-B27 with other human genes. The qPCR analysis demonstrated an increase in the HLA-B27 expression by 1.65 fold in RA compared to normal control. ROC analysis indicated that HLA-B27 expression could efficiently differentiate RA from normal, supporting its potential use as diagnostic molecular biomarkers. The GENT2 revealed that HLA-B27 expression levels vary across different tumor types, most notably in heart tissue. The gene-gene interaction network revealed that KIR3DL1, KIR3DS1, LILRB1, B2M and LILRA1 were the leading genes showing the highest correlations with the HLA-B27. Our results indicate that HLA-B27 gene is involved in the RA pathogenesis and it can be used as a molecular biomarker for the diagnosis of RA. Our findings could lead to the discovery of novel diagnostic, preventive and therapeutic strategies.
G. S. Firestein, "Evolving concepts of rheumatoid arthritis," Nature, vol. 423, pp. 356-361, 2003. doi:10.1038/nature01661
S. E. Gabriel, "The epidemiology of rheumatoid arthritis," Rheumatic disease clinics of north America, vol. 27, pp. 269-281, 2001. doi: 10.1016/s0889-857x(05)70201-5
B. M. Köhler, J. Günther, D. Kaudewitz, and H.-M. Lorenz, "Current therapeutic options in the treatment of rheumatoid arthritis," Journal of Clinical Medicine, vol. 8, p. 938, 2019. doi: 10.3390/jcm807-0938
H. U. Scherer, T. Häupl, and G. R. Burmester, "The etiology of rheumatoid arthritis," Journal of autoimmunity, vol. 110, p. 102400, 2020. doi: 10.1016/j.jaut.2019.102400
T. C. Messemaker, T. W. Huizinga, and F. Kurreeman, " Immunogenetics of rheumatoid arthritis: understanding functional implications," Journal of autoimmunity, vol. 64, pp. 74-81, 2015. doi: 10.1016/j.jaut.2015.07.007
C. M. Weyand and J. J. Goronzy, "The immunology of rheumatoid arthritis," Nature immunology, vol. 22, pp. 10-18, 2021. doi: 10.1038/s41590-020-00816-x
E. G. Favalli, F. Ingegnoli, O. De Lucia, G. Cincinelli, R. Cimaz, and R. Caporali, "COVID-19 infection and rheumatoid arthritis: Faraway, so close!," Autoimmunity reviews, vol. 19, p. 102523, 2020. doi: 10.1016/j.autrev.2020.102523
M. J. Peters, I. E. van der Horst-Bruinsma, B. A. Dijkmans, and M. T. Nurmohamed, "Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis," in Seminars in arthritis and rheumatism, 2004, pp. 585-592. doi: 10.1016/j.semarthrit-.2004.07.010
D. Van der Woude, J. J. Houwing?Duistermaat, R. E. Toes, T. W. Huizinga, W. Thomson, J. Worthington, et al., "Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis," Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, vol. 60, pp. 916-923, 2009. doi: 10.1002/art.24385
J. Smolen, D. Aletaha, and I. McInnes, "Rheumatoid arthritis. Lancet Lond Engl 388: 2023-2038," ed, 2016. doi: 10.1016/S0140-6736(16)30173-8
Y. Okada, D. Wu, G. Trynka, T. Raj, C. Terao, K. Ikari, et al., "Genetics of rheumatoid arthritis contributes to biology and drug discovery," Nature, vol. 506, pp. 376-381, 2014. doi: 10.1038/-nature12873.
L. E. Dedmon, "The genetics of rheumatoid arthritis," Rheumatology, vol. 59, pp. 2661-2670, 2020. doi: 10.1093/-rheumatology/keaa232
J. Hammer, F. Gallazzi, E. Bono, R. W. Karr, J. Guenot, P. Valsasnini, et al., "Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association," The Journal of experimental medicine, vol. 181, pp. 1847-1855, 1995. doi: 10.1084/jem.181.5.1847
P. K. Gregersen, J. Silver, and R. J. Winchester, "The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis," Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, vol. 30, pp. 1205-1213, 1987. doi: 10.1002/-art.1780301102
M. A. Khan, "HLA-B27 and its pathogenic role," JCR: Journal of Clinical Rheumatology, vol. 14, pp. 50-52, 2008. doi: 10.1097/RHU.0b013e3181637-a38
D. Wakefield, D. Clarke, and P. McCluskey, "Recent developments in HLA B27 anterior uveitis," Frontiers in Immunology, vol. 11, p. 608134, 2021. doi: 10.3389/fimmu-.2020.608134
P. Bowness, "HLA-B27," Annual review of immunology, vol. 33, 2015. doi: 10.1146/annurev-immunol-032414-112110
Y. M. Chung, H. T. Liao, K. C. Lin, Y. C. Lin, C. T. Chou, C. H. Chen, et al., "Prevalence of spondyloarthritis in 504 Chinese patients with HLA?B27?associated acute anterior uveitis," Scandinavian journal of rheumatology, vol. 38, pp. 84-90, 2009. doi: 10.1080/03009740802385423
A. M. Braakenburg, H. W. De Valk, J. De Boer, and A. Rothova, "Human Leukocyte Antigen-B27-associated uveitis: Long-term follow-up and gender differences," American journal of ophthalmology, vol. 145, pp. 472-479, 2008. doi: 10.1016/j.ajo.2007.11.009
M. Adam, A. N. Erkan, D. Arslan, B. Leblebici, L. Özlüo?lu, and M. Nafiz Akman, "High-frequency sensorineural hearing loss in patients with ankylosing spondylitis: is it an extrarticuler feature of disease?," Rheumatology international, vol. 28, pp. 413-417, 2008. doi: 10.1007/s00296-007-0458-7
D. Aletaha and J. S. Smolen, "Diagnosis and management of rheumatoid arthritis: a review," Jama, vol. 320, pp. 1360-1372, 2018. doi: 10.1001/jama.2018.13103
M. C. Hochberg, R. W. Chang, I. Dwosh, S. Lindsey, T. Pincus, and F. Wolfe, "The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis," Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, vol. 35, pp. 498-502, 1992. doi: 10.1002/art.1780350502
A. Kurata, M. Yamada, S. I. Ohno, S. Inoue, H. Hashimoto, K. Fujita, et al., "Expression level of microRNA-200c is associated with cell morphology in vitro and histological differentiation through regulation of ZEB1/2 and E-cadherin in gastric carcinoma," Oncol Rep, vol. 39, pp. 91-100, Jan 2018. doi: 10.3892/or.2017.6093
M. A. Bon, A. van Oeveren-Dybicz, and F. A. van den Bergh, "Genotyping of HLA-B27 by real-time PCR without hybridization probes," Clinical chemistry, vol. 46, pp. 1000-1002, 2000. doi.org/10.1093/-clinchem/46.7.1000
T. D. Schmittgen and K. J. Livak, "Analyzing real-time PCR data by the comparative C T method," Nature protocols, vol. 3, p. 1101, 2008. doi: 10.1038-/nprot.2008.73
Y. Nätterkvist, "Development of a PCR method to detect HLA-B27 in ankylosing spondylitis," 2012.
S.-J. Park, B.-H. Yoon, S.-K. Kim, and S.-Y. Kim, "GENT2: an updated gene expression database for normal and tumor tissues," BMC medical genomics, vol. 12, pp. 1-8, 2019. Doi:10.1186/s12920 -019-0514-7
M. Franz, H. Rodriguez, C. Lopes, K. Zuberi, J. Montojo, G. D. Bader, et al., "GeneMANIA update 2018," Nucleic acids research, vol. 46, pp. W60-W64, 2018. doi: 10.1093/nar/gky311
M. D. Ruopp, N. J. Perkins, B. W. Whitcomb, and E. F. Schisterman, "Youden Index and optimal cut?point estimated from observations affected by a lower limit of detection," Biometrical Journal: Journal of Mathematical Methods in Biosciences, vol. 50, pp. 419-430, 2008. doi: 10.1002/bimj.200710415
R. Deshmukh, "Rheumatoid arthritis: pathophysiology, current therapeutic strategies and recent advances in targeted drug delivery system," Materials Today Communications, p. 105877, 2023. doi: 10.3390/cells10113017
M. H. Nicknam, M. Mahmoudi, A. A. Amirzargar, M. G. Hakemi, F. Khosravi, A. R. Jamshidi, et al., "Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis," Iranian Journal of Allergy, Asthma and Immunology, pp. 19-24, 2008. PMID: 18322308
E. Diyarbakir, N. Eyerci, M. Melikoglu, A. Topcu, and I. Pirim, "HLA B27 subtype distribution among patients with ankylosing spondylitis in eastern Turkey," Genetic testing and molecular biomarkers, vol. 16, pp. 456-458, 2012. DOI: 10.1089/gtmb.2011-.0183
K. Esalat-Manesh, M. Taghadosi, and A. Arj, "A survey on the frequency of HLA-B27 in patients engaged with seronegative spondyloarthropathies in Kashan, Iran," Zahedan Journal of Research in Medical Sciences, vol. 17, 2015. https://doi.org-/10.17795/-zjrms983.
H. Yazici, I. Schreuder, S. Yurdakul, and F. Ozbakir, "HLA-B27 in Turkish patients with rheumatoid arthritis," Annals of the Rheumatic Diseases, vol. 46, p. 718, 1987. doi: 10.1136/ard.46-.9.718
N. R. Ziade, "HLA B27 antigen in Middle Eastern and Arab countries: systematic review of the strength of association with axial spondyloarthritis and methodological gaps," BMC Musculoskeletal Disorders, vol. 18, pp. 1-5, 2017. doi: 10.1186/s12891 -017-1639-5.
K. N. Mustafa, M. Hammoudeh, and M. A. Khan, "HLA-B27 prevalence in Arab populations and among patients with ankylosing spondylitis," The Journal of Rheumatology, vol. 39, pp. 1675-1677, 2012. DOI: 10.3899/jrheum.120403
A. Yamaguchi, N. Tsuchiya, H. Mitsui, M. Shiota, A. Ogawa, K. Tokunaga, et al., "Association of hla?b39 with hla?b27?negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in japanese patients," Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, vol. 38, pp. 1672-1677, 1995. DOI: 10.1002/art.-1780381120
C. Perricone, F. Ceccarelli, and G. Valesini, "An overview on the genetic of rheumatoid arthritis: a never-ending story," Autoimmunity reviews, vol. 10, pp. 599-608, 2011. https://doi.org/10.3390/life-11060524
Y. Kochi, A. Suzuki, and K. Yamamoto, "Genetic basis of rheumatoid arthritis: a current review," Biochemical and biophysical research communications, vol. 452, pp. 254-262, 2014. DOI: 10.1016/j.bbrc.2014.07.085
S. Sardar, A. Kerr, D. Vaartjes, E. R. Moltved, E. Karosiene, R. Gupta, et al., "The oncoprotein TBX3 is controlling severity in experimental arthritis," Arthritis research & therapy, vol. 21, pp. 1-17, 2019. DOI: 10.1186/s13075-018-1797-3
R. M. Plenge, L. Padyukov, E. F. Remmers, S. Purcell, A. T. Lee, E. W. Karlson, et al., "Replication of putative candidate-gene associations with rheumatoid arthritis in> 4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4," The American Journal of Human Genetics, vol. 77, pp. 1044-1060, 2005. DOI:10.1086/498651
L. Padyukov, "Genetics of rheumatoid arthritis," in Seminars in immunopathology, 2022, pp. 47-62. Doi: 10.1007/s00281-022-00912-0
L. Mellemkjær, M. Linet, G. Gridley, M. Frisch, H. Møller, and J. Olsen, "Rheumatoid arthritis and cancer risk," European journal of cancer, vol. 32, pp. 1753-1757, 1996. DOI: 10.1016/0959-8049(96)-00210-9
A. Parikh-Patel, R. H. White, M. Allen, and R. Cress, "Risk of cancer among rheumatoid arthritis patients in California," Cancer Causes & Control, vol. 20, pp. 1001-1010, 2009. DOI: 10.1007/s10552-009-9298-y
Y. J. Chen, Y. T. Chang, C. B. Wang, and C. Y. Wu, "The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan," Arthritis & Rheumatism, vol. 63, pp. 352-358, 2011. DOI: 10.1002/art.30134
X. Pundole and M. E. Suarez-Almazor, "Cancer and rheumatoid arthritis," Rheumatic Disease Clinics, vol. 46, pp. 445-462, 2020. DOI: 10.1016/j.rdc.-2020.05.003
E. Rajaei, H. Haybar, K. Mowla, and Z. D. Zayeri, "Metformin one in a million efficient medicines for rheumatoid arthritis complications: Inflammation, osteoblastogenesis, cardiovascular disease, malignancies," Current rheumatology reviews, vol. 15, pp. 116-122, 2019. DOI: 10.2174/1573397-114666180717145745
J. Kishikawa, K. Kawai, N. H. Tsuno, S. Ishihara, H. Yamaguchi, E. Sunami, et al., "Characteristics and prognosis of colorectal cancer associated with rheumatic disease," International Surgery, vol. 100, pp. 783-789, 2015. doi: 10.9738/INTSURG-D-14-00154.1
S. Bergamaschi, E. Morato, M. Bazzo, F. Neves, S. Fialho, G. Castro, et al., "Tumor markers are elevated in patients with rheumatoid arthritis and do not indicate presence of cancer," International Journal of Rheumatic Diseases, vol. 15, pp. 179-182, 2012. DOI: 10.1111/j.1756-185X.2011.01671.x
T. A. Simon, A. Thompson, K. K. Gandhi, M. C. Hochberg, and S. Suissa, "Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis," Arthritis research & therapy, vol. 17, pp. 1-10, 2015. doi: 10.1186/s13075-015-0728-9.
H.-W. Tseng, L.-Y. Lu, H.-C. Lam, K.-W. Tsai, W.-C. Huang, and Y.-L. Shiue, "The influence of disease-modifying anti-rheumatic drugs and corticosteroids on the association between rheumatoid arthritis and skin cancer: a nationwide retrospective case-control study in Taiwan," Clin Exp Rheumatol, vol. 36, pp. 471-8, 2018.
E. Schaafsma, C. M. Fugle, X. Wang, and C. Cheng, "Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy," British Journal of Cancer, vol. 125, pp. 422-432, 2021. DOI: 10.1038/s41416-021-01400-2
N. Aptsiauri and F. Garrido, "The Challenges of HLA Class I Loss in Cancer Immunotherapy: Facts and Hopes," Clinical Cancer Research, vol. 28, pp. 5021-5029, 2022. DOI: 10.1158/10780432.-CCR-21-3501
H. Liang, T. Lu, H. Liu, and L. Tan, "The Relationships between HLA-A and HLA-B Genes and the Genetic Susceptibility to
Copyright (c) 2023 Karzan Ghafur Khidhir, Baban Ahmad, Dana Khdr Sabir
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.