Shedding Light on the Role of ERAP1 in Axial Spondyloarthritis

Saad, Mohamed A; Abdul-Sattar, Amal B; Abdelal, Ibrahim T; Baraka, Ahmed

doi:10.7759/cureus.48806

Cited by 4 publications

(4 citation statements)

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“…Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a vital role in clarifying important biological pathways in AS pathogenesis, mainly linked to human leukocyte antigen B27 (HLA-B27) positive cases, by influencing peptides binding to class I molecules of the major histocompatibility complex (MHC) ( 50 ). ERAP1’s interaction with HLA-B27 influences the peptide processing crucial for disease susceptibility in AS.…”

Section: Discussionmentioning

confidence: 99%

Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers

Zhang,

Liu,

Lai

et al. 2024

Front. Immunol.

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BackgroundAnkylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or biomarkers to prevent AS, addressing the need for innovative and safe treatments.MethodsWe analyzed extensive data from protein quantitative trait loci (pQTLs) with up to 1,949 instrumental variables (IVs) and selected the top single-nucleotide polymorphism (SNP) associated with AS risk. Utilizing a two-sample Mendelian randomization (MR) approach, we assessed the causal relationships between identified proteins and AS risk. Colocalization analysis, functional enrichment, and construction of protein-protein interaction networks further supported these findings. We utilized phenome-wide MR (phenMR) analysis for broader validation and repurposing of drugs targeting these proteins. The Drug-Gene Interaction database (DGIdb) was employed to corroborate drug associations with potential therapeutic targets. Additionally, molecular docking (MD) techniques were applied to evaluate the interaction between target protein and four potential AS drugs identified from the DGIdb.ResultsOur analysis identified 1,654 plasma proteins linked to AS, with 868 up-regulated and 786 down-regulated. 18 proteins (AGER, AIF1, ATF6B, C4A, CFB, CLIC1, COL11A2, ERAP1, HLA-DQA2, HSPA1L, IL23R, LILRB3, MAPK14, MICA, MICB, MPIG6B, TNXB, and VARS1) that show promise as therapeutic targets for AS or biomarkers, especially MAPK14, supported by evidence of colocalization. PhenMR analysis linked these proteins to AS and other diseases, while DGIdb analysis identified potential drugs related to MAPK14. MD analysis indicated strong binding affinities between MAPK14 and four potential AS drugs, suggesting effective target-drug interactions.ConclusionThis study underscores the utility of MR analysis in AS research for identifying biomarkers and therapeutic drug targets. The involvement of Th17 cell differentiation-related proteins in AS pathogenesis is particularly notable. Clinical validation and further investigation are essential for future applications.

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Section: Discussionmentioning

confidence: 99%

Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers

Zhang,

Liu,

Lai

et al. 2024

Front. Immunol.

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“…Saad et al, in a recent study, outlined the significance of ERAP1 polymorphisms in axial spondyloarthritis (axSpA), indicating that their impact on axSpA may differ across diverse ethnic populations. Despite the established epistatic relationship between these polymorphisms and HLA-B27 in several studies, additional research is warranted across various ethnic backgrounds [ 49 , 50 ].…”

Section: Role Of Erap1 In Human Pathogenesismentioning

confidence: 99%

The Role of Aminopeptidase ERAP1 in Human Pathology—A Review

Țiburcă,

Zaha,

Jurca

et al. 2024

CIMB

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Aminopeptidases are a group of enzymatic proteins crucial for protein digestion, catalyzing the cleavage of amino acids at the N-terminus of peptides. Among them are ERAP1 (coding for endoplasmic reticulum aminopeptidase 1), ERAP2 (coding for endoplasmic reticulum aminopeptidase 2), and LNPEP (coding for leucyl and cystinyl aminopeptidase). These genes encoding these enzymes are contiguous and located on the same chromosome (5q21); they share structural homology and functions and are associated with immune-mediated diseases. These aminopeptidases play a key role in immune pathology by cleaving peptides to optimal sizes for binding to the major histocompatibility complex (MHC) and contribute to cellular homeostasis. By their ability to remove the extracellular region of interleukin 2 and 6 receptors (IL2, IL6) and the tumor necrosis factor receptor (TNF), ERAP1 and ERAP2 are involved in regulating the innate immune response and, finally, in blood pressure control and angiogenesis. The combination of specific genetic variations in these genes has been linked to various conditions, including autoimmune and autoinflammatory diseases and cancer, as well as hematological and dermatological disorders. This literature review aims to primarily explore the impact of ERAP1 polymorphisms on its enzymatic activity and function. Through a systematic examination of the available literature, this review seeks to provide valuable insights into the role of ERAP1 in the pathogenesis of various diseases and its potential implications for targeted therapeutic interventions. Through an exploration of the complex interplay between ERAP1 and various disease states, this review contributes to the synthesis of current biomedical research findings and their implications for personalized medicine.

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Mesahel,

Fotoh,

Hadhoud

et al. 2024

Mol Biol Rep

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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.

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Shedding Light on the Role of ERAP1 in Axial Spondyloarthritis

Cited by 4 publications

References 122 publications

Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers

Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers

The Role of Aminopeptidase ERAP1 in Human Pathology—A Review

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

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