Abstract
HLA-II molecules are critical in triggering human immune response, especially in activating CD4+ T cells. HLA-DP, belonging to HLA-II molecules, draws increasing attention for its role in presentation of viral antigen and autoantigen to T cells. Researches reported single nucleotide polymorphism (SNP) of HLA-DP associated with HBV infection and autoimmune diseases such as SLE. However, little is known about the relationship between HLA-DP and rheumatoid arthritis (RA). Rs9277535 is located in 3′ UTR region of HLA-DPB1, a subunit of HLA-DP, and was reported to affect HLA-DP mRNA expression. In the present study, we explored the relationship between gene polymorphism of rs9277535 in HLA-DPB1 and RA susceptibility and progression. Samples from 254 patients with RA and 391 age- and sex-matched healthy controls were collected and genotyped by a polymerase chain reaction-high-resolution melting (PCR-HRM) assay. Serological tests (anti-CCP, rheumatoid factor, C-reactive protein, anti-keratin antibody) were detected by laboratory assays. Strong association was observed between SNP rs9277535 in HLA-DP and RA susceptibility (allele frequency distribution: OR = 1.409, 95%CI = 1.121–1.773, P = 0.004). Further validation was provided by disease model analysis (recessive model: OR = 1.889, 95%CI = 1.194–2.990, P = 0.008; dominant model: OR = 1.464, 95%CI = 1.050–2.041, P = 0.025; additive model: OR = 2.208, 95%CI = 1.335–3.652, P = 0.003). Allele A was correlated to increased risk of RA. Serological test results demonstrated patients carrying allele A of rs9277535 had elevated serum anti-CCP antibody level. The present study provided evidence that HLA-DP gene polymorphism associated with RA susceptibility. Allele A of rs9277535 in HLA-DP correlated to increased risk of RA and elevated serum anti-CCP level.
Similar content being viewed by others
Abbreviations
- RA:
-
Rheumatoid arthritis
- SNP:
-
Single nucleotide polymorphism
- SE:
-
Shared epitopes
- Anti-CCP:
-
Anti-cyclic citrullinated peptide antibody
- RF:
-
Rheumatoid factor
- CRP:
-
C-reactive protein
- AKA:
-
Anti-keratin antibody
- PCR-HRM:
-
Polymerase chain reaction-high-resolution melting
References
Tobon GJ, Youinou P, Saraux A (2010) The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. J Autoimmun 35(1):10–14. https://doi.org/10.1016/j.jaut.2009.12.009
Zeng XF, Zhu S, Tan AC, Xie XP (2013) Disease burden and quality of life of rheumatoid arthritis in China: a systematic review. Chin J Evid-based Med 03:300–307 (In Chinese)
Yarwood A, Huizinga TW, Worthington J (2016) The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford, England) 55(2):199–209. https://doi.org/10.1093/rheumatology/keu323
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
Orozco G, Barton A (2010) Update on the genetic risk factors for rheumatoid arthritis. Expert Rev Clin Immunol 6(1):61–75
Chen L, Huang Z, Yang B, Cai B, Su Z, Wang L (2015) Association of E26 transformation specific sequence 1 variants with rheumatoid arthritis in Chinese Han population. PLoS One 10(8):e0134875. https://doi.org/10.1371/journal.pone.0134875
Snir O, Gomez-Cabrero D, Montes A, Perez-Pampin E, Gomez-Reino JJ, Seddighzadeh M, Klich KU, Israelsson L, Ding B, Catrina AI, Holmdahl R, Alfredsson L, Klareskog L, Tegner J, Gonzalez A, Malmstrom V, Padyukov L (2014) Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis. Arthritis Res Ther 16(4):414. https://doi.org/10.1186/s13075-014-0414-3
Rodriguez-Rodriguez L, Lamas JR, Varade J, Tornero-Esteban P, Abasolo L, de la Concha EG, Jover JA, Urcelay E, Fernandez-Gutierrez B (2012) Combined influence of genetic and environmental factors in age of rheumatoid arthritis onset. Rheumatol Int 32(10):3097–3102. https://doi.org/10.1007/s00296-011-2090-9
Wang J, Zhang H, Wang GQ, Quan Y (2016) HLA-DRB1 gene polymorphisms and its associations with rheumatoid arthritis in Chinese Han women of Shaanxi province, northwest of China. Int J Immunogenet 43(1):25–31. https://doi.org/10.1111/iji.12242
Ytterberg AJ, Joshua V, Reynisdottir G, Tarasova NK, Rutishauser D, Ossipova E, Haj Hensvold A, Eklund A, Skold CM, Grunewald J, Malmstrom V, Jakobsson PJ, Ronnelid J, Padyukov L, Zubarev RA, Klareskog L, Catrina AI (2015) Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann Rheum Dis 74(9):1772–1777. https://doi.org/10.1136/annrheumdis-2013-204912
Viatte S, Plant D, Han B, Fu B, Yarwood A, Thomson W, Symmons DP, Worthington J, Young A, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD, Raychaudhuri S, Barton A (2015) Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA 313(16):1645–1656. https://doi.org/10.1001/jama.2015.3435
Zhou Y, Tan L, Que Q, Li H, Cai L, Cao L, Ye Q, Xiong J (2013) Study of association between HLA-DR4 and DR53 and autoantibody detection in rheumatoid arthritis. J Immunoass Immunochem 34(2):126–133. https://doi.org/10.1080/15321819.2012.690357
Liao Y, Cai B, Li Y, Chen J, Ying B, Tao C, Zhao M, Ba Z, Zhang Z, Wang L (2015) Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China. Liver Int: Off J Int Assoc Study Liver 35(3):886–896. https://doi.org/10.1111/liv.12643
Liu X, Yang B, Li L, Cai B, Liao Y, Li L, Wu Z, Wang L (2016) Association of HLA-DP/DQ and STAT4 polymorphisms with ankylosing spondylitis in Southwest China. Int Immunopharmacol 39:10–15. https://doi.org/10.1016/j.intimp.2016.06.033
Zhang J, Zhan W, Yang B, Tian A, Chen L, Liao Y, Wu Y, Cai B, Wang L (2017) Genetic polymorphisms of rs3077 and rs9277535 in HLA-DP associated with systemic lupus erythematosus in a Chinese population. Sci Rep 7:39757. https://doi.org/10.1038/srep39757
Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, Kubo M, Tsunoda T, Kamatani N, Kumada H, Puseenam A, Sura T, Daigo Y, Chayama K, Chantratita W, Nakamura Y, Matsuda K (2009) A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 41(5):591–595. https://doi.org/10.1038/ng.348
Hosaka T, Suzuki F, Kobayashi M, Fukushima T, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H (2015) HLA-DP genes polymorphisms associate with hepatitis B surface antigen kinetics and seroclearance during nucleot(s)ide analogue therapy. Liver Int: Off J Int Assoc Study Liver 35(4):1290–1302. https://doi.org/10.1111/liv.12652
Field J, Browning SR, Johnson LJ, Danoy P, Varney MD, Tait BD, Gandhi KS, Charlesworth JC, Heard RN, Stewart GJ, Kilpatrick TJ, Foote SJ, Bahlo M, Butzkueven H, Wiley J, Booth DR, Taylor BV, Brown MA, Rubio JP, Stankovich J (2010) A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis. PLoS One 5(10):e13454. https://doi.org/10.1371/journal.pone.0013454
Seidl C, Koch U, Brunnler G, Buhleier T, Frank R, Moller B, Markert E, Koller-Wagner G, Seifried E, Kaltwasser JP (1997) HLA-DR/DQ/DP interactions in rheumatoid arthritis. Eur J Immunogenet: Off J British Soc Histocompatibility Immunogenet 24(5):365–376
Furukawa H, Oka S, Shimada K, Sugii S, Hashimoto A, Komiya A, Fukui N, Nagai T, Hirohata S, Setoguchi K, Okamoto A, Chiba N, Suematsu E, Miyashita T, Migita K, Suda A, Nagaoka S, Tsuchiya N, Tohma S (2013) Association of increased frequencies of HLA-DPB1*05:01 with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese rheumatoid arthritis and systemic lupus erythematosus patients. PLoS One 8(1):e53910. https://doi.org/10.1371/journal.pone.0053910
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69 (9):1580–1588. doi:https://doi.org/10.1136/ard.2010.138461
Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, Aletaha D, van Riel PL (2009) Validation of the 28-joint disease activity score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 68(6):954–960. https://doi.org/10.1136/ard.2007.084459
Lauterbach N, Crivello P, Wieten L, Zito L, Groeneweg M, Voorter CE, Fleischhauer K, Tilanus MG (2014) Allorecognition of HLA-DP by CD4+ T cells is affected by polymorphism in its alpha chain. Mol Immunol 59(1):19–29. https://doi.org/10.1016/j.molimm.2013.12.006
O'Brien TR, Kohaar I, Pfeiffer RM, Maeder D, Yeager M, Schadt EE, Prokunina-Olsson L (2011) Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver. Genes Immun 12(6):428–433. https://doi.org/10.1038/gene.2011.11
Klareskog L, Widhe M, Hermansson M, Ronnelid J (2008) Antibodies to citrullinated proteins in arthritis: pathology and promise. Curr Opin Rheumatol 20(3):300–305. https://doi.org/10.1097/BOR.0b013e3282fbd22a
van Venrooij WJ, van Beers JJ, Pruijn GJ (2008) Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann N Y Acad Sci 1143:268–285. https://doi.org/10.1196/annals.1443.013
Szekanecz Z, Soos L, Szabo Z, Fekete A, Kapitany A, Vegvari A, Sipka S, Szucs G, Szanto S, Lakos G (2008) Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets? Clin Rev Allergy Immunol 34(1):26–31. https://doi.org/10.1007/s12016-007-8022-5
Skogh T (2005) Does a positive anti-CCP test identify a distinct arthritis entity? Arthritis research & therapy 7(6):230–232. https://doi.org/10.1186/ar1836
Engelmann R, Eggert M, Neeck G, Mueller-Hilke B (2010) The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides. Rheumatology (Oxford, England) 49(10):1862–1866. https://doi.org/10.1093/rheumatology/keq179
Szodoray P, Szabo Z, Kapitany A, Gyetvai A, Lakos G, Szanto S, Szucs G, Szekanecz Z (2010) Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. Autoimmun Rev 9(3):140–143. https://doi.org/10.1016/j.autrev.2009.04.006
Kapitany A, Szabo Z, Lakos G, Aleksza M, Vegvari A, Soos L, Karanyi Z, Sipka S, Szegedi G, Szekanecz Z (2008) Associations between serum anti-CCP antibody, rheumatoid factor levels and HLA-DR4 expression in Hungarian patients with rheumatoid arthritis. Isr Med Assoc J: IMAJ 10(1):32–36
Acknowledgments
This work was supported by the National Natural Science Foundation of China 81202354 to ZCH, 81301496 to BY, 81501816 to QN, and 81601830 to JLZ.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosures
None.
Ethical standards
This study has been approved by the Ethics Committee of West China Hospital and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All the participants gave their informed consent prior to their inclusion in the study.
Rights and permissions
About this article
Cite this article
Huang, Z., Niu, Q., Yang, B. et al. Genetic polymorphism of rs9277535 in HLA-DP associated with rheumatoid arthritis and anti-CCP production in a Chinese population. Clin Rheumatol 37, 1799–1805 (2018). https://doi.org/10.1007/s10067-018-4030-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-018-4030-5