Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory disorder that belongs to the group of spondyloarthritis (SpA). It was found that single nucleotide polymorphisms (SNPs) of endoplasmic reticulum aminopeptidase (ERAP1 and ERAP2) genes influence the risk of ankylosing spondylitis, the most common form of SpA and the risk of psoriasis. Our purpose was to investigate the possible association of ERAP1 and ERAP2 gene SNPs with psoriatic arthritis susceptibility in Romanian population. Subsequent analyses included patients’ subgroups according to HLA-B27 status. Psoriatic arthritis patients (N = 98) and random healthy controls (N = 139) were genotyped for ERAP1/2 genes SNPs rs30187, rs27044, rs2910686, and rs2248374 by TaqMan Allelic Discrimination Assays. An additional control group (N = 108; 100% HLA-B27 positive) was used for subsequent analyses. The results showed the association of rs2248374 SNP of ERAP2 gene with the risk of PsA, especially for HLA-B27 negative disease (p = 0.02; OR 1.59). ERAP2 haplotype GT (rs2248374/rs2910686) was significantly under-represented in PsA patients than in controls (43 vs. 55%; p = 0.02). The analysis of ERAP1 SNPs in HLA-B27 positive controls and PsA subgroup showed strong evidence of association for rs30187 (p = 0.005; OR 2.73) and for CC rs30187/rs27044 haplotype (47% in patients vs. 70.5% in controls; p = 0.006). In conclusion, we found a significant association of ERAP2 with PsA and HLA-B27 negative PsA, while ERAP1 association was restricted only to HLA-B27 positive disease. To our knowledge, this is the first study that investigated ERAP2 polymorphisms in relation to PsA susceptibility.
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References
Andres AM, Dennis MY, Kretzschmar WW et al (2010) Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet 6:e1001157
Cherciu M, Popa LO, Bojinca M et al (2013) Functional variants of ERAP1 gene are associated with HLA-B27 positive spondyloarthritis. Tissue Antigens 82:192–196
Cifaldi L, Romania P, Lorenzi S et al (2012) Role of endoplasmic reticulum aminopeptidases in health and disease: from infection to cancer. Int J Mol Sci 13:8338–8352
Cortes A, Hadler J, Pointon JP et al (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45:730–738
Evans DM, Spencer CC, Pointon JJ et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767
Evnouchidou I, Kamal RP, Seregin SS et al (2011) Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J Immunol 186:1909–1913
Harden JL, Krueger JG, Bowcock AM (2015) The immunogenetics of psoriasis: a comprehensive review. J Autoimmun 64:66–73
Jadon D, Tillett W, Wallis D et al (2013) Exploring ankylosing spondylitis-associated ERAP1, IL23R and IL12B gene polymorphisms in subphenotypes of psoriatic arthritis. Rheumatology 52:261–266
Julia A, Tortosa R, Hernanz JM et al (2012) Risk variants for psoriasis vulgaris in a large case–control collection and association with clinical subphenotypes. Hum Mol Genet 21:4549–4557
Kenna TJ, Robinson PC, Haroon N (2015) Endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis. Rheumatology 54:1549–1556
Kim WY, Lee JB, Kim HY et al (2015) Endoplasmic reticulum aminopeptidase 2 is highly expressed in papillary thyroid microcarcinoma with cervical lymph node metastasis. J Cancer Res Ther 11:443–446
Lee S, Mendelsohn A, Sarnes E (2010) The burden of psoriatic arthritis: a literature review from a global health systems perspective. Pharm Ther 35:680–689
Mpakali A, Giastas P, Mathioudakis N et al (2015) Structural basis for antigenic peptide recognition and processing by endoplasmic reticulum (ER) aminopeptidase 2. J Biol Chem 290:26021–26032
O’Rielly DD, Rahman P (2014) Genetics of psoriatic arthritis. Best Pract Res Clin Rheumatol 28:673–685
Palmer JB, Li Y, Herrera V et al (2016) Treatment patterns and costs for anti-TNFalpha biologic therapy in patients with psoriatic arthritis. BMC Musculoskelet Disord 17:261
Popa OM, Bojinca M, Bojinca V et al (2010) Distribution of HLA-B27 in Romanian spondyloarthritides patients. Int J Immunogenet 37:513–516
Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Reeves E, Colebatch-Bourn A, Elliott T et al (2014) Functionally distinct ERAP1 allotype combinations distinguish individuals with ankylosing spondylitis. Proc Natl Acad Sci USA 111:17594–17599
Robinson PC, Costello ME, Leo P et al (2015) ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis 74:1627–1629
Strange A, Capon F, Spencer CC et al (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42:985–990
Strom TM, Wienker TF (2016) DeFinetti program. http://ihg.gsf.de/cgi-bin/hw/hwa1.pl. Accessed 30 May 2016
Stuart PE, Nair RP, Tsoi LC et al (2015) Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet 97:816–836
Tanioka T, Hattori A, Masuda S et al (2003) Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem 278:32275–32283
Tsoi LC, Spain SL, Knight J et al (2012) Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet 44:1341–1348
Yang Q, Liu H, Qu L et al (2013) Investigation of 20 non-HLA (human leucocyte antigen) psoriasis susceptibility loci in Chinese patients with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol 168:1060–1065
Yin X, Low HQ, Wang L et al (2015) Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility. Nat Commun 6:6916
Zervoudi E, Saridakis E, Birtley JR et al (2013) Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses. Proc Natl Acad Sci USA 110:19890–19895
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This research was supported by TC28350/2013 grant from Carol Davila University of Medicine and Pharmacy, Romania.
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Popa, O.M., Cherciu, M., Cherciu, L.I. et al. ERAP1 and ERAP2 Gene Variations Influence the Risk of Psoriatic Arthritis in Romanian Population. Arch. Immunol. Ther. Exp. 64 (Suppl 1), 123–129 (2016). https://doi.org/10.1007/s00005-016-0444-4
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DOI: https://doi.org/10.1007/s00005-016-0444-4