Behçet Hastalığı ile İnterlökin-4 gen (VNTR) Polimorfizmi Arasındaki İlişkinin Araştırılması

Year 2021, , 27 - 32, 03.04.2021

Ayça Kocaağa , Güneş Çakmak Genç , Sevim Karakaş Çelik , Emel Hazinedar , Ahmet Dursun

https://doi.org/10.29058/mjwbs.763529

Abstract

Amaç: Behçet hastalığı (BH); mukokutanöz bulguların ön planda olduğu deri, göz, eklemler,
gastrointestinal ve merkezi sinir sisteminin çeşitli inflamatuar lezyonları ile karakterize sistemik
bir vaskülittir. Sitokinlerin BH patogenezinde önemli rolleri olduğu ve sitokin üretiminin genetik
polimorfizmlerden etkilenebileceği bilindiğinden bu çalışmada IL-4gen (değişken sayılı ardışık tekrarlar-
VNTR) polimorfizmi ile BH arasındaki ilişkinin araştırılması amaçlanmıştır.
Gereç ve Yöntemler: Bu çalışmaya ‘Uluslararası Behçet Hastalığı Çalışma Grubu’ tanı kriterlerine
göre tanı almış 74 Behçet hastası ve 100 sağlıklı kontrol dahil edilmiştir. IL-4 geni VNTR (rs79071878)
polimorfizmi spesifik primerler kullanılarak PZR-RFLP (polimeraz zincir reaksiyonu sınırlama fragman
uzunluğu polimorfizmi) yöntemi ile genotiplenmiştir. Behçet hastaları ve kontrol grupları IL-4 gen VNTR
polimorfizmi açısından genotip ve alel dağılımlarına göre analiz edilmiştir. Ayrıca hastalar bazı klinik
bulgularına göre genotip ve alel dağılımlarına göre karşılaştırılmıştır.
Bulgular: IL-4 geni VNTR (rs79071878) polimorfizmi genotip ve alel dağılımları açısından Behçet hastaları
ve sağlıklı kontroller arasında istatistiksel olarak anlamlı bir fark bulunamamıştır(sırasıyla p=0.332
ve p=0.445). Hastalar bazı klinik özelliklerine göre gruplandırıldığında daIL-4 geni VNTR polimorfizmi
açısından gruplar arasında istatistiksel olarak anlamlı bir fark gözlenmemiştir. Gastrointestinal sistem
(GİS) tutulumu olan hastalarda P2P2 genotip frekansının GİS tutulumu olmayan hastalara göre daha
yüksek olduğu ancak bu farkın istatistiksel açıdan anlamlı olmadığı tespit edilmiştir (%90,0 ve %68,8;
p=0.052).
Sonuç: Bulgularımız IL-4 geni VNTR polimorfizminin BH gelişimi ve klinik bulguları ile ilişkili olmadığını
göstermiştir. Behçet hastalığı ve IL-4 geni ile ilgili sınırlı araştırmalar olması nedeniyle bu çalışma
literatüre önemli bir katkı sağlayacaktır.

Keywords

Behçet hastalığı, IL-4 geni, polimeraz zincir reaksiyonu, polimorfizm, değişken sayılı ardışık tekrarlar

Supporting Institution

Hiçbir kurum veya firmadan finansal destek alınmamıştır.

Investigation of the Relationship Between Behçet’s Disease and Interleukin-4gene (VNTR) Polymorphism

Abstract

Aim: Behçet’s disease (BD); is a systemic vasculitis characterized by various inflammatory lesions of
the mucocutaneous, skin, eyes, joints, gastrointestinal and central nervous system. gene polymorphisms, this study was aimed to investigate the relationship between IL-4 gene (variable number tandem repeats-VNTR) polymorphism and pathogenesis of BD.
Material and Methods: This study included 74 Behçet patients diagnosed according to the ‘International Behçet’s Disease Study Group’ criteria and 100 healthy controls. Genomic DNA was isolated from peripheral venous blood. IL-4 gene VNTR polymorphism was genotyped by the PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) method using specific primers. Behçet’s patients and control groups were analyzed for IL-4 gene VNTR (variable number tandem repeats-) polymorphism according to their genotype and allele distributions. In addition, with regard to some clinical findings, patients were compared according to their genotype and allele distribution.
Results: The distribution of genotype and allele frequencies were not statistically different between BD patients and healthy controls (p>0.05). When we examined genotype and allele frequencies of IL-4 gene VNTR polymorphism according to some clinical characteristics, we did not observed a statistically significant association between the BD patients. It was found that the P2P2 genotype frequency was higher in patients with positive gastrointestinal system (GIS) involvement compared to GIS negative patients, but this difference was not statistically significant (90.0% vs 68.8%; p = 0.052).
Conclusion: Our findings showed that IL-4 gene VNTR polymorphism was not related to the development and clinical manifestations of BD. The present study is expected to make an important contribution to the literature since there are limited researches on BD and IL-4 gene.

Keywords

Behçet’s disease, IL-4 gene, Polymerase chain reaction, Polymorphism, Variable number of tandem repeats

References

• 1. Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behcet’s disease: A comprehensive review. J Autoimmun 2015; 64: 137-148.
• 2. Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulaç M, Tunc R, Urgancioglu M, Dişçi R. Prevalence of Behcet’s disease in Istanbul Turkey. Int J Dermatol 2003; 42: 803-806.
• 3. Gül A. Behçet’s disease as an autoinflammatory disorder. Curr Drug Targets Inflamm Allergy 2005; 4(1): 81-83.
• 4. Dilek K, Ozcimen AA, Saricaoglu H et al. Cytokine gene polymorphisms in Behcet’s disease and their association with clinical and laboratory findings. Clin Exp Rheumatol 2009; 27: 73-78.
• 5. Park H, Li Z, Yang XO et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133-1141.
• 6. Harrington LE, Hatton RD, Mangan PR et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-1132.
• 7. Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K. Cytokine profile in Behcet’s disease patients. Relationship with disease activity. Scand J Rheumatol 2002; 31:205-210.
• 8. Kubo M, Yamashita M, Abe R et al. CD28 costimulation accelerates IL-4 receptor sensitivity and IL-4-mediated Th2 differentiation. J Immunol 1999; 163: 2432-2442.
• 9. Ozçimen AA, Dilek K, Bingöl U, et al. IL-1 cluster gene polymorphisms in Turkish patients with Behçet’s disease. Int J Immunogenet 2011; 38(4): 295-301.
• 10. Pérez-Suárez TG, Gutiérrez-Robledo LM, Ávila-Funes JA, Acosta JL, EscamillaTilch M, Padilla-Gutiérrez JR, et al. VNTR polymorphisms of the IL-4 and IL-1RN genes and their relationship with frailty syndrome in Mexican communitydwelling elderly. Aging Clin Exp Res 2016; 28: 823-832.
• 11. Zaaber I, Mestiri S, Hammedi H, et al. Association of Interleukin-1B and Interleukin-4 gene variants with autoimmune thyroid diseases in tunisian population. Immunol Invest 2016; 45(4): 284-297.
• 12. Inoue T, Kira R, Nakao F, et al. Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis. Arch Neurol 2002; 59(5): 822-827.
• 13. Vargiolu M, Silvestri T, Bonora E, et al. Interleukin-4/ interleukin-4 receptor gene polymorphisms in hand osteoarthritis. Osteoarthritis Cartilage 2010; 18(6): 810-816.
• 14. Wu KH, Peng CT, Li TC, et al. Interleukin 4, interleukin 6 and interleukin 10 polymorphisms in children with acute and chronic immune thrombocytopenic purpura. Br J Haematol 2005; 128(6): 849-852.
• 15. Rong H, He X, Wang L, He Y, Kang L, Jin T. Associations between polymorphisms in the IL-4 gene and renal cell carcinoma in Chinese Han population. Oncotarget 2017; 8(47): 82078-82084.
• 16. Wang Y, Li H, Wang X, Gao F, Yu L, Chen X. Association between four SNPs in IL-4 and the risk of gastric cancer in a Chinese population. Int J Mol Epidemiol Genet 2017; 8(4): 45-52.
• 17. Sadeghi A, Davatchi F, Shahram F, et al. Serum profiles of cytokines in Behcet’s disease. J Clin Med 2017; 6(5): 49.
• 18. Genevay S, Di Giovine FS, Perneger TV, et al. Association of interleukin-4 and interleukin-1B gene variants with Larsen score progression in rheumatoid arthritis. Arthritis Rheum 2002; 47(3): 303-309.
• 19. Ozsoy AZ, Cakmak B, Nacar MC, Cetin A, Demirturk F, Dogru YH, Karakus N, Yigit S. MTHFR and IL-4 gene polymorphisms are not associated with primary dysmenorrhea in young adults. International Journal of Human Genetics 2015; 15(2): 73-79.
• 20. Al-Eitan LN, Rababa’h DM, Alghamdi MA, Khasawneh RH. The influence of an IL-4 variable number tandem repeat (VNTR) polymorphism on breast cancer susceptibility. Pharmgenomics Pers Med 2019; 12: 201-207.
• 21. Chua KH, Kee BP, Tan SY, Lian LH. Genetic polymorphisms of interleukin-4 third intron region in the malaysian patients with systemic lupus erythematosus. Journal of Medical Sciences 2008; 8: 437-442.
• 22. Vasudevan R, Norhasniza MN, Patimah I. Association of variable number of tandem repeats polymorphism in the IL-4 gene with end-stage renal disease in Malaysian patients. Genet Mol Res 2011;10(2): 943-947.
• 23. Nursal AF, Tekcan A, Kaya SU, Sezer O, Yigit S. Interleukin- 1Ra rs2234663 and Interleukin-4 rs79071878 polymorphisms in familial mediterranean fever. Gene. 2016; 582(2): 173-177.
• 24. Inanir A, Tural S, Yigit S, et al. Association of IL-4 gene VNTR variant with deep venous thrombosis in Behçet’s disease and its effect on ocular involvement. Mol Vis 2013; 19: 675-683.