چاپ صفحه |  صفحه نخست سامانه |  چکیده مقاله |  نویسندگان |  دانلود مقاله | دانشگاه علوم پزشکی تبریز |
| Background: 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. Methods: 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. 568 | EBRAZEH et al. 1 | INTRODUC TION Ankylosing spondylitis (AS) is a chronic autoimmune disease and is characterized by involvement of spine and sacroiliac joints, which causes spinal deformities, increased disability, and mortality.1 A bulk of research has suggested a significant role for genetic variations in the etiology and pathogenesis of AS,2,3 in spite of the remarkable involvement of environmental factors as well as aberrant epigenetic regulations.4-8 The pathogenesis of AS is complicated, and earlier research concentrated on the misfolding of the human leukocyte antigen (HLA)-B27 molecule in disease susceptibility; however, genetic studies have proposed that HLA-B27 accounts for a small part of the overall AS risk.9 Epidemiological investigations has shown that the HLA-B27 gene is carried by almost 90% of AS patients, whereas only 1%-5% of individuals carrying the HLA-B27 gene will be affected with AS in the future.10 These observations imply the involvement of non-HLA genes in AS risk. Endoplasmic reticulum aminopeptidase (ERAP) 2 is an enzyme that belongs to the zinc-containing metallopeptidase family and the corresponding gene is located on the chromosome 5q15. This enzyme is found within the endoplasmic reticulum, which is involved in priming peptides during the antigen presentation pathway via the major histocompatibility complex class I.11 In comparison to ERAP1, data are lacking about the attribution of ERAP2 polymorphisms with AS predisposition. 4,12,13 A number of genetic polymorphisms in the ERAP2 gene have been attributed to produce alterations in the protein structure and function. The AS-protective ERAP2 gene single nucleotide polymorphism (SNP) rs224837414 alters the splicing site in the exon 10, leading to synthesis of a lengthy exon 10 transcript.15 As a loss of enzyme polymorphism, rs2248374 causes no protein expression of ERAP2 and has been attributed with downregulation of major histocompatibility complex class I molecule levels on the cell surface.15 Another variant is rs2549782 SNP, which confers a modulation in the specificity as well as functional velocity of the enzymatic activity of ERAP2.14,16 ERAP2 gene rs2549782 SNP shows a linkage disequilibrium (LD) with other ERAP2 SNPs, including rs2548538, rs2287988, rs1056893, and rs2248374, which are marker SNPs that constitute A and B haplotypes that are associated with protein expression of ERAP2.15 In addition, ERAP2 gene rs17408150 leads to substitution of a T with an A at codon 669 (p.Leu- 669Gln), which alters the leucine residue to glutamine, producing a significant effect on the ERAP2 enzyme function.17 Association of ERAP1 SNPs with AS susceptibility in Iranian patients has already been reported in our previous studies.18-21 Furthermore, we recently indicated the association of ERAP2 gene SNPs with AS susceptibility in HLA-B27- positive individuals.22 With respect to the involvement of genetic variations in the alteration of ERAP2, it seems that evaluation of such SNPs is worthwhile. Hence, this study aims to determine the associations of ERAP2 gene rs2548538, rs2287988, and rs17408150 SNPs, for the first time to the best of our knowledge, in an Iranian AS population. Furthermore, the possible role of these SNPs was investigated in the control of inflammatory and immunomodulatory mediators in AS. 2 | MATERIAL S A ND M E THODS 2.1 | Study participants In this investigation, 250 individuals with AS and 250 persons as healthy controls were included (Table 1). The 1984 modified New York Criteria were used to diagnose AS.23 Healthy controls had no background diseases or history of AS or other autoimmune diseases, neither in them nor in family members, and were matched for age and gender with the case group. AS patients were selected from individuals who were recruited to Shahid Rajaee and Emam Reza Hospitals affiliated with Alborz and Tabriz University of Medical Sciences, Iran and outpatient Rheumatology Clinics of the Tabriz University of Medical Sciences during 2015 to 2020. Approval of Results: 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. Conclusions: 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. |
| نویسنده | نفر چندم مقاله |
|---|---|
| مریم همت زاده | هفتم |
| فرهاد جدیدی نیارق | دهم |
| نام فایل | تاریخ درج فایل | اندازه فایل | دانلود |
|---|---|---|---|
| Association of the genetic variants in the endoplasmic reticulum aminopeptidase 2 gene with ankylosing spondylitis susceptibility.pdf | 1400/02/04 | 2183259 | دانلود |
