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Association of ERAP2 Polymorphisms in Colombian HLA-B27+ Or HLA-B15+ Patients with Spa and Its Relationship with Clinical Presen

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Association of ERAP2 Polymorphisms in Colombian HLA-B27+ Or HLA-B15+ Patients with Spa and Its Relationship with Clinical Presen RMD Open: first published as 10.1136/rmdopen-2020-001250 on 10 September 2020. Downloaded from Spondyloarthritis Original research Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance John Londono ,1,2 Ana M Santos,1 Juan C Rueda,1 Enrique Calvo-Paramo,3 Ruben Burgos-Vargas,4 Gilberto Vargas-Alarcon,5 Nancy Martinez-Rodriguez,6 Sofia Arias-Correal,1 Guisselle-Nathalia Muñoz,1 Diana Padilla,1 Francy Cuervo,1 Viviana Reyes-Martinez,1 Santiago Bernal-Macías ,1 Catalina Villota-Eraso,1 Luz M Avila-Portillo,1,2 Consuelo Romero,2 Juan F Medina7 To cite: Londono J, Santos AM, ABSTRACT Key messages Rueda JC, et al. Association of Objective To determine the association between ERAP2 polymorphisms in endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 Colombian HLA-B27+ or HLA- What is already known about this subject? single-nucleotide polymorphisms (SNPs) and human B15+ patients with SpA and its ► ERAP1 and ERAP2 polymorphisms have been leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with relationship with clinical associated with SpA: ERAP1 SNPs preferentially spondyloarthritis (SpA). presentation: axial or peripheral with HLA-B27+ patients and ERAP2 SNPs with HLA- Methods predominance. RMD Open 104 patients with SpA according to B27− patients. 2020;6:e001250. doi:10.1136/ Assessment of Spondyloarthritis International Society rmdopen-2020-001250 criteria were included in the study. HLA typing was What does this study add? performed by PCR. The polymorphisms were determined ► In this study, conducted on a group of Latin American Received 24 March 2020 Revised 23 July 2020 by real-time PCR on genomic DNA using customised patients with SpA, particular ERAP2 but not ERAP1 Accepted 1 August 2020 probes for SNPs rs27044, rs17482078, rs10050860 and SNP haplotypes were found to be associated with http://rmdopen.bmj.com/ rs30187 in ERAP1, and rs2910686, rs2248374 and either HLA-B27+ or HLA-B15+ patients with SpA. rs2549782 in ERAP2. ► The results of previous research have confirmed that Results 70 of the104 patients with SpA were HLA- the presence of the HLA-B27 allele is related to the B27+ and 34 were HLA-B15+. The distribution of development of a predominantly axial disease, ERAP1 and ERAP2 SNPs between the HLA-B15+ and whereas the HLA-B15 allele is associated with HLA-B27+ patients with SpA did not reveal differences. a predominantly peripheral disease. Likewise, no differences in the frequencies of ERAP1 How might this impact on clinical practice? SNP haplotypes and alleles HLA-B15 or HLA-B27 were ► The association of ERAP2 SNP haplotypes with HLA- on September 29, 2021 by guest. Protected copyright. found. Interestingly, however, the frequencies of three B27+ or with HLA-B15+ patients with SpA could particular haplotypes formed by ERAP2 SNPs condition the pattern of clinical presentation of the rs2549782/rs2248374/rs2910686 varied between HLA- disease, preferentially axial or peripheral disease. B15+ and HLA-B27+ patients: the ERAP2 SNPs ► The results of this study deserve to be validated haplotype TGT was more common in HLA-B15+ further with other studies involving a larger number patients with SpA (OR 2.943, 95% CI 1.264 to 6.585; of patients with SpA. P=0.009), whereas the ERAP2 SNP haplotypes TGC © Author(s) (or their and CAT were more associated with HLA-B27+ employer(s)) 2020. Re-use patients with SpA: (OR 4.483, 95% CI 1.524 to 13.187; permitted under CC BY-NC. No commercial re-use. See rights p=0.003) and (OR 9.014, 95% CI 1.181 to 68.807; INTRODUCTION and permissions. Published p=0.009), respectively. Spondyloarthritis (SpA) are a heterogeneous Conclusion by BMJ. An association was found between HLA-B15+ group of chronic inflammatory joint diseases, patients with SpA and haplotype TGT of ERAP2 SNPs. On the For numbered affiliations see characterised by axial and peripheral manifes- end of article. other hand, HLA-B27+ patients with SpA were associated tations, as recognised by the implementation with ERAP2 haplotypes TGC and CAT. These associations of the new classification criteria proposed by Correspondence to could be related to the clinical presentation of the disease, John Londono; specifically with a peripheral or axial predominance, the group Assessment of Spondyloarthritis [email protected]. respectively. International Society (ASAS). In the axial pre- co sentation, the sacroiliac joints are particularly Londono J, et al. RMD Open 2020;6:e001250. doi:10.1136/rmdopen-2020-001250 1 RMD Open: first published as 10.1136/rmdopen-2020-001250 on 10 September 2020. Downloaded from RMD Open affected, followed by an ascending compromise of the The objective of the present study was to establish the spine. The peripheral manifestations are characterised association of polymorphisms of ERAP1 and ERAP2 genes by asymmetric oligoarthritis and enthesitis of the lower in Colombian patients with SpA with HLA-B27+ or HLA- – limbs.1 3 B15+, and to evaluate how this association could be The origin of SpA is considered to be multifactorial, related to the clinical presentation of the disease, specifi- where a genetic susceptibility background coupled cally with axial or peripheral predominance. with the presence of certain environmental triggers stimulates the onset of the disease.4 Similar to other rheumatic diseases, a polygenic origin has been pro- MATERIALS AND METHODS posed, where the strongest association is established Patients and clinical assessment with molecules of the major histocompatibility com- A group of 104 patients with diagnosis of SpA accord- plex (MHC-I), specifically the human leukocyte anti- ing to the European Spondyloarthropathy Study gen B27 (HLA-B27).5 While HLA-B27 molecule is Group (ESSG) criteria16 and positive for either HLA- recognised to confer genetic susceptibility to develop B27 or HLA-B15 were included in the current study of SpA (with positivity in about 25–40% of patients), and ERAP SNPs. Patients were collected from an outpati- several hypotheses have been proposed to explain its ent clinic of SpA of two referral hospitals in Bogotá, participation in the development of the disease, none from January 2009 to December 2016. Subsequently, of them clearly explain the role of this molecule for patients were classified according to the new ASAS the pathogenesis of the disease.5 criteria for the classification of the axial and periph- Advances in genetics and studies in large populations eral SpA. Demographic and clinical data, including have additionally established associations of more than 40 Bath Ankylosing Spondylitis Disease Activity Index genes unrelated to the MHC and the development of (BASDAI),17 functional capacity (Bath Ankylosing SpA. The most consistent of them are the genes of the Spondylitis Functional Index (BASFI)),18 global dis- endoplasmic reticulum aminopeptidase (ERAP) type 1 ease activity assessed by physicians and by patients and ERAP2.67These enzymes include a single class of through a visual analogue scale (VAS), and joints pleiotropic proteases with localisation in the endoplasmic affected were recorded.10 Mander’sindexwasusedto reticulum (ER). They play an important role in the pro- evaluate involved enthesis inflammations.19 For each cess of N-terminal fraction of the antigenic peptide that patient, routine laboratory tests were assessed. will occupy the MHC-I molecules for presentation at the In a previous study,14 our patients with SpA and – cell surface to CD8+ lymphocytes.8 11 a control group of 100 healthy subjects on the list of ERAP1 and ERAP2 have unique peptidic specificities. transplant donors with similar socio-demographic char- Evidence indicates that ERAP2 is involved in antigenic acteristics as our SpA population were compared for the cleavage in ER and forms a repertoire of ligands for MHC- analysis of the Hardy-Weinberg equilibrium by using the http://rmdopen.bmj.com/ I molecules that are different from those generated by Arlequin statistical software version 3.5.20 Allele fre- ERAP1. This leads to an efficient and coordinated pre- quency (AF) among the patient population was calcu- sentation of a wide variety of peptides when these lated using updated versions of the Genepop enzymes act together.12 Program.21 Likewise, the increase in the frequency of The association of ERAP1 polymorphisms with SpA HLA-B27 or HLA-B15 in the group of patients with SpA, appeared to be related with the predisposition to develop compared to the aforementioned healthy control popu- the disease in HLA-B27+ individuals and ERAP2 poly- lation, was determined with the Genepop Program as morphisms in individuals with other non-HLA-B27 described.14 on September 29, 2021 by guest. Protected copyright. alleles. However, Robinson et al found an association of ERAP2 polymorphisms with ankylosing spondylitis (AS) Imaging 13 in both HLA-B27+ and HLA-B27− patients. In all patients, a plain anterior pelvic X-ray and MRI of the Currently, our research group is focused on the parti- sacroiliac joints with T1 sequence and fat suppression cular genetics and phenotypes of the patients with SpA technique were obtained. The images were evaluated by of Latin America ancestry (in Colombia). Previously, we a radiologist with musculoskeletal expertise who was analysed the presence of HLA-A, HLA-B and HLA-DR blinded to the clinical information. The X-ray readings molecules in 189 Colombian patients with a diagnosis of were made following the recommendations for popula- SpA plus 100 healthy subjects who were on the list of tion studies according to the Atlas of Standard transplant donors, and had similar socio-demographic Radiographs.22 MRI was evaluated looking for acute characteristics as our SpA population. In addition to the changes in the joints.23 expected increase in the frequency of HLA-B27, we also found an increased frequency of HLA-B15 in our HLA genotyping patients with SpA.14 Also, we reported a clear association Genomic DNA was extracted from peripheral blood leu- between HLA-B27 with axial SpA including AS, and kocytes with a Wizard Genomic DNA Purification Kit HLA-B15 with peripheral SpA including undifferen- (Promega, Cat.
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