Diagnostic role of lncRNA GAS5 and its genetic polymorphisms rs2067079, rs6790 and rs17359906 in rheumatoid arthritis

Elamir,Azza M.; Senara,Soha; Abdelghaffar,Noha Khalifa; Gaber,Sylvana N.; El Sayed,Hassan Salem

doi:10.3892/br.2021.1469

Diagnostic role of lncRNA GAS5 and its genetic polymorphisms rs2067079, rs6790 and rs17359906 in rheumatoid arthritis

Authors:
- Azza M. Elamir
- Soha Senara
- Noha Khalifa Abdelghaffar
- Sylvana N. Gaber
- Hassan Salem El Sayed
View Affiliations

Affiliations: Medical Biochemistry Department, Faculty of Medicine, Fayoum University, Fayoum 63616, Egypt, Department of Rheumatology and Rehabilitation, Faculty of Medicine, Fayoum University, Fayoum 63616, Egypt, Department of Clinical Pathology, Faculty of Medicine, Fayoum University, Fayoum 63616, Egypt, Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum 63616, Egypt
Published online on: September 14, 2021 https://doi.org/10.3892/br.2021.1469
Article Number: 93

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to detect the serum levels of long non‑coding RNA (lncRNA) growth arrest‑specific 5 (GAS5) in patients with rheumatoid arthritis (RA) and healthy controls, and determine the association between the rs2067079, rs6790, and rs17359906 single‑nucleotide polymorphisms (SNPs) of lncRNA GAS5 gene with RA risk in the Egyptian population. Reverse transcription‑quantitative PCR and real‑time PCR were used to measure the serum levels of lncRNA GAS5 and genotype the two distinct alleles at the SNP sites of lncRNA GAS5 gene in 200 patients with RA and 150 controls. The mean serum levels of lncRNA GAS5 were significantly lower in the patients with RA compared with the controls (P<0.0001), and the serum levels of lncRNA GAS5 were significantly negatively associated with erythrocyte sedimentation rate, C‑reactive protein levels and anti‑cyclic citrullinated peptide levels in the patients with RA. The TT genotype of rs2067079 SNP was significantly associated with a decreased risk of RA [TT vs. CC: Odds ratio (OR)=2.358; 95% confidence interval (CI), 1.114‑5.131; P=0.045) and the risk of rs2067079 SNP reduced with a recessive pattern (TT vs. TC + CC: OR=2.374; 95% CI, 1.091‑5.123; P=0.037). rs6790 SNP was associated with RA risk in the recessive model (AA vs. GA + GG: OR=2.55; 95% CI=1.39‑5.32; P=0.02). No significant associations were noted between the rs17359906 SNP and RA risk (P>0.05) or between the lncRNA GAS5 levels and their respective genotypes at the three SNPs in patients with RA (all P>0.05). Based on the results of the present study, lncRNA GAS5 may serve as a biomarker for the early detection of RA. The TT genotype of rs2067079 SNP was significantly associated with a decreased risk of RA, and a reduced risk of rs2067079 SNP was observed with a recessive pattern. rs6790 SNP was associated with RA risk in the recessive model.

View Figures

View References

1	Lee DM and Weinblatt ME: Rheumatoid arthritis. Lancet. 358:903–911. 2001.PubMed/NCBI View Article : Google Scholar
2	Solus JF, Chung CP, Oeser A, Li C, Rho YH, Bradley KM, Kawai VK, Smith JR and Stein CM: Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: A candidate gene analysis. Clin Rheumatol. 34:1375–1382. 2015.PubMed/NCBI View Article : Google Scholar
3	Yamanaka H: TNF as a target of inflammation in rheumatoid arthritis. Endocr Metab Immune Disord Drug Targets. 15:129–134. 2015.PubMed/NCBI View Article : Google Scholar
4	Wu GC: Immunoregulation function of long noncoding RNA in rheumatic diseases. Chin J Dis Control Prev. 20:1165–1171. 2016.
5	Messemaker TC, Frank-Bertoncelj M, Marques RB, Adriaans A, Bakker AM, Daha N, Gay S, Huizinga TW, Toes REM, Mikkers HMM and Kurreeman F: A novel long non-coding RNA in the rheumatoid arthritis risk locus TRAF1-C5 influences C5 mRNA levels. Genes Immun. 17:85–92. 2016.PubMed/NCBI View Article : Google Scholar
6	Zhang F, Wu L, Qian J, Qu B, Xia S, La T, Wu Y, Ma J, Zeng J, Guo Q, et al: Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. J Autoimmun. 75:96–104. 2016.PubMed/NCBI View Article : Google Scholar
7	Haywood MEK, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ and Morley BJ: Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun. 7:250–263. 2006.PubMed/NCBI View Article : Google Scholar
8	Wu Y, Zhang F, Ma J, Zhang X, Wu L, Qu B, Xia S, Chen S, Tang Y and Shen N: Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus. Arthritis Res Ther. 17(131)2015.PubMed/NCBI View Article : Google Scholar
9	Kino T, Hurt DE, Ichijo T, Nader N and Chrousos GP: Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 3(ra8)2010.PubMed/NCBI View Article : Google Scholar
10	Mayama T, Marr AK and Kino T: Differential expression of glucocorticoid receptor Noncoding RNA repressor gas5 in autoimmune and inflammatory diseases. Horm Metab Res. 48:550–557. 2016.PubMed/NCBI View Article : Google Scholar
11	Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, et al: Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 506:376–381. 2014.PubMed/NCBI View Article : Google Scholar
12	Kumar V, Wijmenga C and Withoff S: From genome-wide association studies to disease mechanisms: Celiac disease as a model for autoimmune diseases. Semin Immunopathol. 34:567–580. 2012.PubMed/NCBI View Article : Google Scholar
13	Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, et al: 2010 Rheumatoid arthritis classification criteria: An American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 69:1580–1588. 2010.PubMed/NCBI View Article : Google Scholar
14	World Medical Association (WMA): WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. WMA, Helsinki, 1964. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Latest Updated July 9, 2018.
15	Sinton JR: Clinical value of some methods of estimating erythrocyte sedimentation rate. Br Med J. 1:391–393. 1948.PubMed/NCBI View Article : Google Scholar
16	Salazar LA, Hirata MH, Cavalli SA, Machado MO and Hirata RD: Optimized procedure for DNA isolation from fresh and cryopreserved clotted human blood useful in clinical molecular testing. Clin Chem. 44:1748–1750. 1988.PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
18	McInnes IB and Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 365:2205–2219. 2011.PubMed/NCBI View Article : Google Scholar
19	Wu GC, Pan HF, Leng RX, Wang DG, Li XP, Li XM and Ye DQ: Emerging role of long noncoding RNAs in autoimmune diseases. Autoimmun Rev. 14:798–805. 2015.PubMed/NCBI View Article : Google Scholar
20	Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, et al: The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 47:199–208. 2015.PubMed/NCBI View Article : Google Scholar
21	Müller N, Döring F, Klapper M, Neumann K, Schulte DM, Türk K, Schröder JO, Zeuner RA, Freitag-Wolf S, Schreiber S and Laudes M: Interleukin-6 and tumour necrosis factor-α differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis. Cytokine. 68:65–68. 2014.PubMed/NCBI View Article : Google Scholar
22	Zhang Z, Zhu Z, Watabe K, Zhang X, Bai C, Xu M, Wu F and Mo YY: Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ. 20:1558–1568. 2013.PubMed/NCBI View Article : Google Scholar
23	Tu ZQ, Li RJ, Mei JZ and Li XH: Down-regulation of long non-coding RNA GAS5 is associated with the prognosis of hepatocellular carcinoma. Int J Clin Exp Pathol. 7:4303–4309. 2014.PubMed/NCBI
24	Pickard MR and Williams GT: Molecular and cellular mechanisms of action of tumour suppressor GAS5 LncRNA. Genes (Basel). 6:484–499. 2015.PubMed/NCBI View Article : Google Scholar
25	Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, Yosef N, Vaidya VS and Weiner HL: MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest. 125:1069–1080. 2015.PubMed/NCBI View Article : Google Scholar
26	Dong L, Wang X, Tan J, Li H, Qian W, Chen J, Chen Q, Wang J, Xu W, Tao C and Wang S: Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis. J Cell Mol Med. 18:2213–2224. 2014.PubMed/NCBI View Article : Google Scholar
27	Song J, Ahn C, Chun CH and Jin EJ: A long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis. J Orthop Res. 32:1628–1635. 2014.PubMed/NCBI View Article : Google Scholar
28	Wu GC, Li J, Leng RX, Li XP, Li XM, Wang DG, Pan HF and Ye DQ: Identification of long non-coding RNAs GAS5, linc0597 and lnc-DC in plasma as novel biomarkers for systemic lupus erythematosus. Oncotarget. 8:23650–23663. 2017.PubMed/NCBI View Article : Google Scholar
29	Li J, Wu GC, Zhang TP, Yang XK, Chen SS, Li LJ, Xu SZ, Lv TT, Leng RX, Pan HF and Ye DQ: Association of long noncoding RNAs expression levels and their gene polymorphisms with systemic lupus erythematosus. Sci Rep. 7(15119)2017.PubMed/NCBI View Article : Google Scholar
30	Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA and Clayton DG: The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet. 42:68–71. 2010.PubMed/NCBI View Article : Google Scholar
31	Pasmant E, Sabbagh A, Vidaud M and Bièche I: ANRIL, a long noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J. 25:444–448. 2011.PubMed/NCBI View Article : Google Scholar
32	Eftekharian MM, Noroozi R, Komaki A, Mazdeh M, Taheri M and Ghafouri-Fard S: GAS5 genomic variants and risk of multiple sclerosis. Neurosci Lett. 701:54–57. 2019.PubMed/NCBI View Article : Google Scholar
33	Li Q, Ma G, Sun SH, Xu Y and Wang B: Polymorphism in the promoter region of lncRNA GAS5 is functionally associated with the risk of gastric cancer. Clin Res Hepatol Gastroenterol. 42:478–482. 2018.PubMed/NCBI View Article : Google Scholar
34	Wu J, Zhang TP, Zhao YL, Li BZ, Leng RX, Pan HF and Ye DQ: Decreased H19, GAS5, and linc0597 expression and association analysis of related gene polymorphisms in rheumatoid arthritis. Biomolecules. 10(55)2019.PubMed/NCBI View Article : Google Scholar