Association of and Gene Polymorphisms and ERAP2 Protein with the Susceptibility and Severity of Rheumatoid Arthritis in the Ukrainian Population

Overview

Journal Front Immunol

Date 2025 Feb 5

PMID 39906739

Authors

Iryna Kril

Andrzej Wisniewski

Agnieszka Tarnowska

Khrystyna Lishchuk-Yakymovych

Yaryna Bojko

Piotr Kusnierczyk

Valentyna V Chopyak

Izabela Nowak

Affiliations

Soon will be listed here.

Abstract

Introduction: Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. Although RA is chiefly associated with HLA class II, nevertheless some HLA class I associations have also been observed. These molecules present antigenic peptides to CD8+ T lymphocytes and natural killer cells. HLA-I molecules bind their peptide cargo (8-10 amino acids long) in the endoplasmic reticulum. Peptides longer than 10 amino acids are trimmed by the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 to fit the peptide binding groove of the HLA-I molecule. Here, we investigated the possible association of and polymorphisms with RA, and also any possible correlation between serum levels of the ERAP2 protein with disease severity.

Methods: We used Real-Time PCR to genotype and and ELISA test to detect protein.

Results: We found significant associations of rs30187, rs27044, and rs26618, as well as rs2248374, with susceptibility to RA. rs26653 and ERAP2 rs2248374 were also associated with the Disease Activity Score (DAS28), and some polymorphisms were also associated with anti-citrullinated protein or anti-mutated citrullinated vimentin antibodies. RA patients secreted higher concentrations of ERAP2 than controls. Patients with mild disease activity (DAS28 < 3.2) released a concentration of ERAP2 four times lower than that of patients with severe disease activity (DAS28 > 5.1). We detected a higher level of in rheumatoid factor (RF)-positive patients than in RF-negative patients. concentration above 5.85 ng/mL indicated a severe phase of RA.

Conclusions: Some and polymorphisms seem to be related to susceptibility to RA or the severity of the disease. The ERAP2 protein tested in serum could be a valuable biomarker of RA severity.

References

Castro-Santos P, Moro-Garcia M, Marcos-Fernandez R, Alonso-Arias R, Diaz-Pena R . ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. Innate Immun. 2017; 23(5):476-481. DOI: 10.1177/1753425917716527. View

Mizuki N, Inoko H, Ohno S . Molecular genetics (HLA) of Behçet's disease. Yonsei Med J. 1998; 38(6):333-49. DOI: 10.3349/ymj.1997.38.6.333. View

DAlicandro V, Romania P, Melaiu O, Fruci D . Role of genetic variations on MHC class I antigen-processing genes in human cancer and viral-mediated diseases. Mol Immunol. 2018; 113:11-15. DOI: 10.1016/j.molimm.2018.03.024. View

Hamilton F, Mentzer A, Parks T, Baillie J, Davey Smith G, Ghazal P . Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease. Am J Hum Genet. 2023; 110(4):691-702. PMC: 10119032. DOI: 10.1016/j.ajhg.2023.02.008. View

Majorczyk E, Pawlik A, Luszczek W, Nowak I, Wisniewski A, Jasek M . Associations of killer cell immunoglobulin-like receptor genes with complications of rheumatoid arthritis. Genes Immun. 2007; 8(8):678-83. DOI: 10.1038/sj.gene.6364433. View

Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E . Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat Genet. 2013; 45(2):202-7. PMC: 3810947. DOI: 10.1038/ng.2520. View

Alivernini S, Firestein G, McInnes I . The pathogenesis of rheumatoid arthritis. Immunity. 2022; 55(12):2255-2270. DOI: 10.1016/j.immuni.2022.11.009. View

Saric T, Chang S, Hattori A, York I, Markant S, Rock K . An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol. 2002; 3(12):1169-76. DOI: 10.1038/ni859. View

Raychaudhuri S, Sandor C, Stahl E, Freudenberg J, Lee H, Jia X . Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012; 44(3):291-6. PMC: 3288335. DOI: 10.1038/ng.1076. View

10.

Kuiper J, van Setten J, Devall M, Cretu-Stancu M, Hiddingh S, Ophoff R . Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis. Hum Mol Genet. 2018; 27(24):4333-4343. PMC: 6276832. DOI: 10.1093/hmg/ddy319. View

11.

Wisniewski A, Matusiak L, Szczerkowska-Dobosz A, Nowak I, Luszczek W, Kusnierczyk P . The association of ERAP1 and ERAP2 single nucleotide polymorphisms and their haplotypes with psoriasis vulgaris is dependent on the presence or absence of the HLA-C*06:02 allele and age at disease onset. Hum Immunol. 2017; 79(2):109-116. DOI: 10.1016/j.humimm.2017.11.010. View

12.

Gregersen P, Silver J, Winchester R . The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987; 30(11):1205-13. DOI: 10.1002/art.1780301102. View

13.

Li C, Li Y, Yan Z, Dai S, Liu S, Wang X . Polymorphisms in endoplasmic reticulum aminopeptidase genes are associated with cervical cancer risk in a Chinese Han population. BMC Cancer. 2020; 20(1):341. PMC: 7178719. DOI: 10.1186/s12885-020-06832-2. View

14.

Akhtar M, Ali Y, Islam Z, Arshad M, Rauf M, Ali M . Characterization of Rheumatoid Arthritis Risk-Associated SNPs and Identification of Novel Therapeutic Sites Using an Approach. Biology (Basel). 2021; 10(6). PMC: 8227790. DOI: 10.3390/biology10060501. View

15.

Gao S, Xu T, Liang W, Xun C, Deng Q, Guo H . Association of rs27044 and rs30187 polymorphisms in endoplasmic reticulum aminopeptidase 1 gene and ankylosing spondylitis susceptibility: A meta-analysis. Int J Rheum Dis. 2020; 23(4):499-510. DOI: 10.1111/1756-185X.13795. View

16.

Burton P, Clayton D, Cardon L, Craddock N, Deloukas P, Duncanson A . Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007; 39(11):1329-37. PMC: 2680141. DOI: 10.1038/ng.2007.17. View

17.

Harvey D, Pointon J, Evans D, Karaderi T, Farrar C, Appleton L . Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet. 2009; 18(21):4204-12. PMC: 2758148. DOI: 10.1093/hmg/ddp371. View

18.

Yao Y, Liu N, Zhou Z, Shi L . Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations. Hum Immunol. 2019; 80(5):325-334. DOI: 10.1016/j.humimm.2019.02.011. View

19.

Lemire M . On the association between rheumatoid arthritis and classical HLA class I and class II alleles predicted from single-nucleotide polymorphism data. BMC Proc. 2009; 3 Suppl 7:S33. PMC: 2795931. DOI: 10.1186/1753-6561-3-s7-s33. View

20.

Yang S, Liu X, Gao Y, Ding M, Li B, Sun H . Association of single nucleotide polymorphisms in the 3'UTR of ERAP1 gene with essential hypertension in the Northeastern Han Chinese. Gene. 2015; 560(2):211-6. DOI: 10.1016/j.gene.2015.02.005. View