A study of the association between single nucleotide polymorphisms of the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene and the risk of ankylosing spondylitis in Egyptians

Molecular Biology Reports (2024) 51:614 https://doi.org/10.1007/s11033-024-09404-w ORIGINAL ARTICLE A study of the association between single nucleotide polymorphisms of the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene and the risk of ankylosing spondylitis in Egyptians Randa Mohamed Ibrahim Mesahel1 · Dina Salem Fotoh2 Mohamed Farag Ali Assar4 · Mahmoud Mohammed Hadhoud3 · Received: 10 November 2023 / Accepted: 29 February 2024 © The Author(s) 2024 Abstract Background Ankylosing spondylitis (AS) is often regarded as the prototypical manifestation of spondylo-arthropathies that prevalently involves the axial skeleton with the potential attribution of ERAP2 polymorphisms to AS predisposition. The purpose of this study was to determine the genetic association between ERAP2 gene rs2910686, and rs2248374 single nucleotide polymorphisms (SNPs) and the risk of ankylosing spondylitis in the Egyptian population. Methods and results A cross-sectional work involved 200 individuals: 100 AS individuals diagnosed based on modified New York criteria in 1984 with 100 healthy controls matched in age and gender. The study included a comprehensive evaluation of historical data, clinical examinations, and evaluation of the activity of the disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). A comprehensive laboratory and radiological evaluation were conducted, accompanied by an assessment and genotyping of the ERAP2 gene variants rs2248374 and rs2910686. This genotyping was performed utilizing a real-time allelic discrimination methodology.Highly statistically substantial variations existed among the AS patients and the healthy control group regarding rs2910686 and rs2248374 alleles. There was a statistically significant difference between rs2910686 and rs2248374 regarding BASDAI, BASFI, mSASSS, ASQoL, V.A.S, E.S.R, and BASMI in the active AS group. Conclusions ERAP2 gene SNPs have been identified as valuable diagnostic biomarkers for AS patients in the Egyptian population being a sensitive and non-invasive approach for AS diagnosis especially rs2910686. Highly statistically significant variations existed among the AS patients and the healthy control group regarding rs2910686 alleles and genotypes.Further research is recommended to explore the potential therapeutic implications of these SNPs. Keywords Single nucleotide polymorphisms · Endoplasmic reticulum aminopeptidase 2 (ERAP2) gene · Ankylosing spondylitis 1 Chemistry Department, Faculty of Science, Suze Canal University, Ismailia, Egypt 2 Physical medicine, Rheumatology and Rehabilitation department, Faculty of Medicine, Menoufia University, Al Minufiyah, Egypt Mahmoud Mohammed Hadhoud 3 Orthopedic Surgery Department, Faculty of Medicine, Menoufia University, Al Minufiyah, Egypt Mohamed Farag Ali Assar 4 Biochemistry and Molecular Biology Department, Faculty of Science, Menoufia University, Al Minufiyah, Egypt Dina Salem Fotoh ; ; Randa Mohamed Ibrahim Mesahel 13 614 Page 2 of 14 Introduction Ankylosing spondylitis (AS) is widely recognized as the prototypical variant of spondyloarthropathies. It is a persistent autoimmune-inflammatory condition characterized by progressive arthritis that primarily affects young adults. The disease predominantly involves the axial joints including the spine and sacroiliac joints, and is often accompanied by additional manifestations outside the joints, such as psoriasis, uveitis, and inflammatory bowel diseases [1] . Because of the lack of precise understanding of the pathophysiology, it is hypothesized that the clinical progression of AS starts with an initial phase of inflammation, subsequently leading to the development of the formation of new bones that triggers localized osteitis, erosion of cartilage, destruction of bone, and eventual ankylosis. Sacroiliitis and syndesmophytes, known as radiographic AS, may be identified with the use of conventional radiography. However, the early diagnosis of these conditions can be facilitated by using MRI [2]. The human leukocyte antigen (HLA-B27) remains the most effective biomarker for diagnosing AS, whereas C-reactive protein (CRP) serves as the optimal marker for evaluating the extent of the disease, assessing therapy effectiveness, and monitoring structural development. However, it should be noted that HLAB-27 accounts for just 30% of the genetic variables associated with AS, suggesting the presence of other genetic abnormalities implicated in the development of AS [3]. The enzyme known as endoplasmic reticulum aminopeptidase 2 (ERAP2) is situated inside the endoplasmic reticulum. It is classified as a member of the zinc-containing metallopeptidase family, and its corresponding gene is positioned on chromosome 5q15. The involvement of ERAP2 in the process of peptide trimming via the major histocompatibility complex class I throughout the antigen presentation pathway has been observed. In contrast to ERAP1, there is a limitation of evidence on the association between ERAP2 polymorphisms and AS susceptibility [4]. Several genetic variants within the ERAP2 gene have been associated with modifications in the structure and functionality of the protein. The SNP rs2248374 in the ERAP2 gene has been shown to have a protective effect against AS. This SNP specifically affects the splicing location in exon 10 of the gene, resulting in the production of a longer exon 10 transcript [5]. ERAP2 instead has evolved under balancing selection that maintains two haplotypes, one of which undergoes RNA splicing leading to nonsense-mediated decay and loss of protein. Hence, likewise in rodents, wherein the ERAP2 gene is missing, about a quarter of the human population does not express ERAP2 [6]. 13 Molecular Biology Reports The rs2248374 SNP has been previously associated with a reduced risk of AS. This SNP is a functionally significant variation located in the ERAP2 gene, that plays a crucial role in modifying the functional velocity and specificity of ERAP2 functioning during the process of trimming peptides. The rs2910686 SNP located inside the ERAP2 gene has been identified as a gene of functional significance, and its association with AS susceptibility has been established. The association between SNPs in the ERAP1 gene and susceptibility to AS has been reported [7]. The ERAP2 gene variant rs2549782 SNP exhibits linkage disequilibrium (LD) with many other ERAP2 SNPs, such as rs2548538, rs2287988, rs1056893, and rs2248374. These SNPs serve as marker variants that form haplotypes A and B, which are correlated with the protein expression of ERAP2. Furthermore, the ERAP2 gene variant rs17408150 results in a nucleotide substitution from T to A at codon 669, leading to the amino acid change from leucine to glutamine (p.Leu-669Gln). This alteration has been seen to have a significant impact on the functionality of the ERAP2 enzyme [5]. The objective of this work is to investigate the potential genetic correlation b (...truncated)