Abstract
Genetic polymorphisms in the endoplasmic reticulum aminopeptidase gene ERAP2 has been attributed with the etiopathogenesis of ankylosing spondylitis (AS). Here we assessed the association of ERAP2 gene single nucleotide polymorphisms (SNPs) with AS predisposition in Iranian patients and determined their effect on the inflammatory state of the patients. For genotyping of rs2548538, rs2287988, and rs17408150 SNPs using a real-time allelic discrimination approach, DNA was extracted from the whole blood of 250 AS patients and 250 healthy individuals. RNA of the peripheral blood mononuclear cells was separated, cDNA was synthesized, and transcriptional levels of cytokines, including interleukin (IL)-17A, IL-23, IL-10, and transforming growth factor-β, were measured. Enzyme-linked immunosorbent assay was used to measure the serum concentration on the cytokines. Three ERAP2 gene SNPs were not associated significantly with AS risk. Nonetheless, rs2287988 and rs17408150 SNPs showed statistically significant association with susceptibility to the disease in those AS patients who were positive for human leukocyte antigen (HLA)-B27. Transcriptional level and serum concentration of IL-17A and IL-23 were higher, but those of IL-10 were lower in both AS patients and the HLA-B27-positive patient group relative to the control group. Nevertheless, ERAP2 gene SNPs in the HLA-B27-positive AS patients did not affect the transcription level and serum concentration of cytokines. ERAP2 gene rs2287988 and rs17408150 SNPs are associated with susceptibility to AS, but they are probably not determining the levels of IL-17A, IL-23, and IL-10 in this disease.
Highlights
Genetic polymorphisms in the Endoplasmic reticulum aminopeptidase (ERAP) 2 gene has been attributed with the Ankylosing spondylitis (AS) etiopathogenesis
ERAP2 gene rs2287988 and rs17408150 single nucleotide polymorphisms (SNPs) are associated with susceptibility to AS, but they probably are not determining the levels of IL-17A, IL-23, and IL-10 in this disease
The pathogenesis of AS is complicated, and earlier research concentrated on the misfolding of human leukocyte antigen (HLA)-B27 molecule in the disease susceptibility; genetic studies have proposed that HLA-B27 accounts for a small part of the overall AS risk [9]
Summary
Genetic polymorphisms in the Endoplasmic reticulum aminopeptidase (ERAP) 2 gene has been attributed with the Ankylosing spondylitis (AS) etiopathogenesis. Endoplasmic reticulum aminopeptidase (ERAP) 2 is an enzyme that belongs to zn-metallopeptidase family and the corresponding gene is located on the chromosome 5q15 This enzyme is found within the endoplasmic reticulum (ER) that is involved in priming peptides during the antigen presentation pathway via the major histocompatibility complex (MHC) class I [11]. As a loss-of enzyme polymorphism, rs2248374 cause no protein expression of ERAP2 and has been attributed with downregulation of MHC class I molecule levels on the cell surface [15]. Another variant is rs2549782 SNP, that confers a modulation in the specificity as well as functional velocity of the enzymatic activity of ERAP2 [14, 16]. ERAP2 gene rs17408150 leads to substitution of a T with an A at codon 669 (p.Leu669Gln) that alters the leucine residue to glutamine, resulting in a significant effect on the ERAP2 enzyme function [17]
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