Liliia Sh. NAZAROVA, Denis O. KARIMOV, Ksenia V. DANILKO, Viktor A. MALIEVSKY, Akhat B. BAKIROV, Tatiana V. VIKTOROVA

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

Background/aim: The aim of the study was to analyze the relationship of the immune response mediator genes’ polymorphic loci(TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622,CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, PADI4 rs2240336) variants with the methotrexate efficacy in juvenileidiopathic arthritis (JIA).Materials and methods: The study included 274 JIA patients from the Republic of Bashkortostan, Russia. Achieving the AmericanCollege of Rheumatology Pediatric 30 (ACR Pedi 30) response was regarded as the presence of the response to methotrexate (otherwise,as the absence), while achieving clinical remission on medication (Wallace et al., 2011) - as the sufficient response (otherwise, as theinsufficient). Genotyping was conducted by the real-time polymerase chain reaction.Results: Associations with an altered risk of the nonresponse to methotrexate in JIA were observed for the alleles/genotypes of the lociIL10 rs1800872 (in girls) and NFKB1 rs28362491 (in girls); with an altered risk of the insufficient response to methotrexate in JIA – forthe alleles/genotypes of the loci IL1B rs16944 (in boys), CTLA4 rs3087243 (in boys), NFKB1 rs28362491 (in girls) and the haplotypeTNFA rs1800629*A - LTA rs909253*G (in girls).Conclusion: As a result of the study, the relationship of the alleles/genotypes of the IL1B rs16944, IL10 rs1800872, CTLA4 rs3087243,NFKB1 rs28362491 polymorphic loci and the TNFA rs1800629*A - LTA rs909253*G haplotype with the methotrexate efficacy in JIA wasestablished (taking into account the differences by sex).

PDF

___

1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. The Journal of Rheumatology 2004; 31 (2): 390-392.
2. Kim KH, Kim DS. Juvenile idiopathic arthritis: DIAGNOSIS ANd differential diagnosis. Korean Journal of Pediatrics 2010; 53 (11): 931-935. doi: 10.3345/kjp.2010.53.11.931
3. Barut K, Adrovic A, Şahin S, Kasapçopur Ö. Juvenile idiopathic arthritis. Balkan Medical Journal 2017; 34 (2): 90-101. doi: 10.4274/balkanmedj.2017.0111
4. van Dijkhuizen EH, Wulffraat NM. Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatric Rheumatology 2014; 12: 51. doi: 10.1186/1546-0096-12-51
5. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis & Rheumatism 2012; 64 (6): 2012-2021. doi: 10.1002/art.34343
6. Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care & Research 2011; 63 (4): 465-482. doi: 10.1002/acr.20460
7. Albarouni M, Becker I, Horneff G. Predictors of response to methotrexate in juvenile idiopathic arthritis. Pediatric Rheumatology 2014; 12: 35. doi: 10.1186/1546-0096-12-35
8. Roszkiewicz J, Smolewska E. In the pursuit of methotrexate treatment response biomarker in juvenile idiopathic arthritisare we getting closer to personalised medicine? Current Rheumatology Reports 2017; 19 (4): 19. doi: 10.1007/s11926- 017-0646-8
9. Pastore S, Stocco G, Favretto D, De Iudicibus S, Taddio A et al. Genetic determinants for methotrexate response in juvenile idiopathic arthritis. Frontiers in Pharmacology 2015; 6: 52. doi: 10.3389/fphar.2015.00052
10. Pawlik A, Baskiewicz-Masiuk M, Machalinski B, GawronskaSzklarz B. Association of cytokine gene polymorphisms and the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. International Immunopharmacology 2006; 6 (3): 351-357. doi: 10.1016/j. intimp.2005.08.019
11. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World Journal of Orthopedics 2014; 5 (4): 516-536. doi: 10.5312/wjo.v5.i4.516
12. Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C et al. Methotrexate an old drug with new tricks. International Journal of Molecular Sciences 2019; 20 (20): E5023. doi: 10.3390/ijms20205023
13. Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P et al. methotrexate restores regulatory T cell function through demethylation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis & Rheumatology 2015; 67 (5): 1182-1192. doi: 10.1002/art.39031
14. Schmeling H, Horneff G, Benseler SM, Fritzler MJ. Pharmacogenetics: can genes determine treatment efficacy and safety in JIA? Nature Reviews Rheumatology 2014; 10 (11): 682-690. doi: 10.1038/nrrheum.2014.140
15. Cobb J, Cule E, Moncrieffe H, Hinks A, Ursu S et al. Genomewide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. The Pharmacogenomics Journal 2014; 14 (4): 356-364. doi: 10.1038/tpj.2014.3
16. Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A et al. Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenetics and Genomics 2010; 20 (11): 665-676. doi: 10.1097/FPC.0b013e32833f2cd0
17. Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: A comprehensive review. Journal of Autoimmunity 2015; 64: 113-124. doi: 10.1016/j.jaut.2015.08.002
18. Hisa K, Yanagimachi MD, Naruto T, Miyamae T, Kikuchi M et al. PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis. PLoS ONE 2017; 12 (2): e0171961. doi: 10.1371/journal.pone.0171961
19. Grom AA, Murray KJ, Luyrink L, Emery H, Passo MH et al. Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis & Rheumatism 1996; 39 (10): 1703-1710. doi: 10.1002/art.1780391013
20. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care & Research 2011; 63 (7): 929-936. doi: 10.1002/acr.20497
21. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT et al. Preliminary definition of improvement in juvenile arthritis. Arthritis & Rheumatism 1997; 40 (7): 1202-1209. doi: 10.1002/ art.1780400703
22. Wallace CA, Ruperto N, Giannini EH. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. The Journal of Rheumatology 2004; 31 (11): 2290- 2294.
23. Mathew CGP. The isolation of high molecular weight eukaryotic DNA. In: Walker JM (editor). Methods in Molecular Biology, Volume 2: Nucleic Acids. Clifton, NJ, USA: Humana Press; 1984. pp. 31-34. doi: 10.1385/0-89603-064-4:31
24. Liu K, Muse SV. PowerMarker: an integrated analysis environment for genetic marker analysis. Bioinformatics 2005; 21 (9): 2128-2129. doi: 10.1093/bioinformatics/bti282
25. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006; 22 (15): 1928-1929. doi: 10.1093/bioinformatics/btl268
26. McDonald JH. Handbook of Biological Statistics. 3rd ed. Baltimore, MD, USA: Sparky House Publishing; 2014
27. Westfall PH, Young SS. Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment. New York, NY, USA: John Wiley & Sons; 1993.
28. Fagerland MW, Lydersen S, Laake P. Recommended confidence intervals for two independent binomial proportions. Statistical Methods in Medical Research 2015; 24 (2): 224-254. doi: 10.1177/0962280211415469
29. Pociot F, Mølvig J, Wogensen L, Worsaae H, Dalbøge H et al. A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus. Scandinavian Journal of Immunology 1991; 33 (1): 37-49. doi: 10.1111/j.1365-3083.1991.tb02490.x
30. Wang S, Cowley LA, Liu XS. Sex differences in cancer immunotherapy efficacy, biomarkers, and therapeutic strategy. Molecules 2019; 24 (18): pii: E3214. doi: 10.3390/ molecules24183214
31. Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH et al. Single nucleotide polymorphisms in the human interleukin1B gene affect transcription according to haplotype context. Human Molecular Genetics 2006; 15 (4): 519-529
32. Wen AQ, Wang J, Feng K, Zhu PF, Wang ZG et al. Effects of haplotypes in the interleukin 1β promoter on lipopolysaccharide-induced interleukin 1β expression. Shock 2006; 26 (1): 25-30. doi: 10.1097/01.shk.0000223125.56888.c7
33. Nazarova LS, Danilko KV, Malievsky VA, Bakirov AB, Viktorova TV. The immune response mediator genes polymorphic variants as predictors of the etanercept efficacy in juvenile idiopathic arthritis. Russian Open Medical Journal 2018; 7 (2): e0204. doi: 10.15275/rusomj.2018.0204
34. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood 2018; 131 (1): 58-67. doi: 10.1182/blood-2017-06-741033
35. Kasela S, Kisand K, Tserel L, Kaleviste E, Remm A et al. Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells. PLoS Genetics 2017; 13 (3): e1006643. doi: 10.1371/journal. pgen.1006643
36. Pereira SG, Oakley F. Nuclear factor-κB1: Regulation and function. The International Journal of Biochemistry & Cell Biology 2008; 40 (8): 1425-1430. doi: 10.1016/j. biocel.2007.05.004
37. Yang YN, Zhang JY, Ma YT, Xie X, Li XM et al. -94 ATTG insertion/deletion polymorphism of the NFKB1 gene is associated with coronary artery disease in Han and Uygur women in China. Genetic Testing and Molecular Biomarkers 2014; 18 (6): 430-438. doi: 10.1089/gtmb.2013.0431
38. Stegger JG, Schmidt EB, Berentzen TL, Tjønneland A, Vogel U et al. Interaction between obesity and the NFKB1 - 94ins/ delATTG Promoter polymorphism in relation to incident acute coronary syndrome: a follow up study in three independent cohorts. PLoS ONE 2013; 8 (5): e63004. doi: 10.1371/journal. pone.0063004
39. Mangoni AA, Zinellu A, Sotgia S, Carru C, Piga M et al. Protective effects of methotrexate against proatherosclerotic cytokines: a review of the evidence. Mediators of Inflammation 2017; 2017: 9632846. doi: 10.1155/2017/9632846
40. Ma Y, Li L, Shao Y, Bai X, Bai T et al. Methotrexate improves perivascular adipose tissue/endothelial dysfunction via activation of AMPK/eNOS pathway. Molecular Medicine Reports 2017; 15 (4): 2353-2359. doi: 10.3892/mmr.2017.6225
41. Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Human Molecular Genetics 2004; 13 (1): 35-45. doi: 10.1093/hmg/ ddh008