VİTİLİGODA İNTERLÖKİN 18 GEN POLİMORFİZMLERİNİN ANALİZİ

Yıl 2022, Cilt: 3 Sayı: 3, 318 - 322, 31.12.2022

Güneş Çakmak Genç , Sevim Karakaş Çelik , Nilgün Solak Tekin , Tuba Edgünlü , Ümmühani Özel Türkcü , Ahmet Dursun

https://doi.org/10.52831/kjhs.1180771

Öz

Amaç: Vitiligo, fonksiyonel melanositlerin kaybı ile karakterize yaygın bir pigment bozukluğudur. İmmünopatogenezi tam olarak aydınlatılamasa da cilt mikroçevresindeki inflamatuar değişikliklerin ve özellikle sitokin ekspresyonunun artmasının, melanosit disfonksiyonu ve ölümünün temel nedeni olduğu düşünülmektedir. Vitiligonun IFN-γ inhibisyonu kullanılarak tedavisi ile pozitif sonuçlar elde edilmiştir. İnterlökin 18 (IL-18), T hücrelerinde IFN-γ üretimini indükleyen ve Th1 yanıtında rolü olan önemli bir sitokindir. IL18 promotörü, çok sayıda polimorfizm içeren oldukça polimorfik bir bölgedir. Ancak bu polimorfizmlerden birçoğunun IL-18 üretimi ile ilişkili olmadığı bildirilmiştir, sadece promotördeki -137 G/C (rs187238) ve -607 C/A (rs1946518) polimorfizmlerinin promotörün aktivitesini etkilediği ve buna bağlı olarak da IL-18 üretimini etkilediği gösterilmiştir. Ayrıca bu polimorfizmlerin çeşitli otoimmün ve inflamatuar bozukluklarla ilişkili olduğu bildirilmiştir. Bildiğimiz kadarıyla, vitiligo ve IL18 gen polimorfizmleri arasındaki ilişkiyi araştıran hiçbir çalışma yoktur. Bu çalışmada, bu varyantların vitiligoya yatkınlıkla ilişkili olup olmadığının belirlenmesi için vitiligo hastalarında ve kontrol grubunda yukarıda bahsedilen rs187238 ve rs1946518 promotör polimorfizmlerinin sıklığı araştırıldı.
Yöntem: Vitiligo tanılı 89 hasta ve 87 sağlıklı katılımcının, IL18 promotor polimorfizmleri PCR-RFLP yöntemi ile incelendi.
Bulgular: Vitiligo hastaları, kontrol grubu ile karşılaştırıldığında IL18 rs187238 ve rs1946518 polimorfizmleri genotip ve alel frekanslarında anlamlı bir farklılık bulunamadı. IL18 rs187238'in CC genotipi frekansının, vitiligo hastalarında kontrol grubuna göre daha az olduğu görülmekle birlikte bu fark istatistiksel olarak anlamlı değildi (p=0.213). IL18 genindeki iki SNP'nin haplotip analizinde de gruplar arasında istatistiksel anlamlılığa ulaşılamadı (p=0.715).
Sonuç: Sonuç olarak, elde ettiğimiz bulgular IL18 gen polimorfizmlerinin (-137 G/C (rs187238) ve -607 C/A (rs1946518)) vitiligo riski ve aktivitesi ile herhangi bir ilişkisinin olmadığını göstermektedir. Ancak, örneklem sayımızın nispeten küçük olmasından dolayı bulgularımızın ileri çalışmalarda etnik açıdan çeşitlilik içeren büyük örneklem gruplarıyla tekrarlanarak doğrulanması daha anlamlı olacaktır.

Anahtar Kelimeler

Vitiligo, İnterlökin 18, Gen Polimorfizm, rs187238, rs1946518

ANALYSIS OF INTERLEUKIN 18 GENE POLYMORPHISMS IN VITILIGO

Öz

Objective: Vitiligo is a common pigmentary disorder caused by the destruction of functional melanocytes. Its immunopathogenesis is not completely understood, but inflammatory alterations in the skin microenvironment, and particularly increased expression of the cytokines, are thought to be essential regulators of melanocyte dysfunction and death. Treatment of vitiligo using IFN-γ inhibition has given positive responses. Interleukin-18 (IL-18) is a cytokine that plays an important role in the Th1 response, by its ability to induce IFN-γ production in T cells and natural killer cells. The IL18 promoter is highly polymorphic containing several polymorphisms which have been described in the promoter region of IL18. Most of them were not reported to be associated with IL-18 production, only the -137 G/C (rs187238) and -607 C/A (rs1946518) SNPs in the promoter affect its promoter activity and IL-18 production was demonstrated. In addition, these SNPs have been reported to be associated with several autoimmune and inflammatory disorders. To our knowledge, no study has investigated the association between vitiligo and IL18 gene polymorphisms. We investigated the frequencies of the two above-mentioned IL18 promoter alterations in vitiligo patients and control subjects to determine whether these variants might represent susceptibility factors for vitiligo.
Method: IL18 promoter polymorphisms of 89 patients with vitiligo and 87 healthy participants were analyzed by PCR-RFLP method.
Results: There were no significant differences in the genotype and allele frequency of IL18 rs187238, and rs1946518 SNPs when compared to vitiligo patients with healthy subjects. The frequency of the CC genotype of IL18 rs187238 tended to decrease in vitiligo patients compared to healthy subjects but was not statistically significant (p=0.213). In haplotype analysis of two SNPs in the IL18 gene also did not reach statistical significance (p=0.715).
Conclusion: In conclusion, our results suggest that IL18 gene polymorphisms were not played a key role in the pathogenesis of vitiligo. In addition, because of the relatively small number of subjects, our findings are preliminary and need to be validated in further studies with larger sample sizes.

Anahtar Kelimeler

Vitiligo, Interleukin-18, Gene Polymorphisms, rs187238, rs1946518

Kaynakça

• Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet. 2015;386(9988):74-84.
• Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16(3):208-214.
• Spritz RA. The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma. Genome Med. 2010;2(10):78.
• Spritz RA. Modern vitiligo genetics sheds new light on an ancient disease. J Dermatol. 2013;40(5):310-318.
• Sandoval-Cruz M, García-Carrasco M, Sánchez-Porras R, et al. Immunopathogenesis of vitiligo. Autoimmun Rev. 2011;10(12):762-765.
• Harrison P, Pointon JJ, Chapman K, Roddam A, Wordsworth BP. Interleukin-1 promoter region polymorphism role in rheumatoid arthritis: a meta-analysis of IL-1B-511A/G variant reveals association with rheumatoid arthritis. Rheumatology (Oxford). 2008;47(12):1768-1770.
• Biet F, Locht C, Kremer L. Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens. J Mol Med (Berl). 2002;80(3):147-162.
• Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8⁺ T-cell accumulation in the skin. J Invest Dermatol. 2012;132(7):1869-1876.
• Shi F, Erf GF. IFN-γ, IL-21, and IL-10 co-expression in evolving autoimmune vitiligo lesions of Smyth line chickens. J Invest Dermatol. 2012;132(3 Pt 1):642-649.
• Yang L, Wei Y, Sun Y, et al. Interferon-gamma inhibits melanogenesis and ınduces apoptosis in melanocytes: a pivotal role of CD8+ Cytotoxic T lymphocytes in vitiligo. Acta Derm Venereol. 2015;95(6):664-670.
• Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112(1-2):146-152.
• Kalina U, Ballas K, Koyama N, et al. Genomic organization and regulation of the human interleukin-18 gene. Scand J Immunol. 2000;52(6):525-530.
• Kruse S, Kuehr J, Moseler M, et al. Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis. J Allergy Clin Immunol. 2003;111(1):117-122.
• Kuo CT, Leiden JM. Transcriptional regulation of T lymphocyte development and function. Annu Rev Immunol. 1999;17:149-87.
• Imboden MA, Nieters AJ, Bircher M, et al. Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA). Clin Mol Allergy. 2006;4(1):1-9.
• Arimitsu J, Hirano T, Higa S, et al. IL-18 gene polymorphisms affect IL-18 production capability by monocytes. Biochem Biophys Res Commun. 2006;342(4):1413-1416.
• Kretowski A, Mironczuk K, Karpinska A, et al. Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes. 2002;51(11):3347-3349.
• Gurram VC, Polipalli SK, Karra VK, et al. Genetic polymorphism of interleukin-18 gene promoter region in rheumatoid arthritis patients from southern India. J Clin Diagn Res. 2014;8(6):SC01-SC04.
• Izakovicova Holla L, Hrdlicková B, Schüller M, et al. Haplotype analysis of the interleukin-18 gene in Czech patients with allergic disorders. Hum Immunol. 2010;71(6):592-597.
• RK, K MS, G KK, et al. Evaluation of Hs-CRP levels and interleukin 18 (-137G/C) promoter polymorphism in risk prediction of coronary artery disease in first degree relatives [published correction appears in PLoS One. 2015;10(5):e0127609.
• Taheri M, Hashemi M, Eskandari-Nasab E, et al. Association of -607 C/A polymorphism of IL-18 gene (rs1946518) with breast cancer risk in Zahedan, Southeast Iran. Prague Med Rep. 2012;113(3):217-222.
• Liu JM, Liu JN, Wei MT, et al. Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population. Genet Mol Res. 2013;12(1):820-829.
• Farjadfar A, Mojtahedi Z, Ghayumi MA, Erfani N, Haghshenas MR, Ghaderi A. Interleukin-18 promoter polymorphism is associated with lung cancer: a case-control study. Acta Oncol. 2009;48(7):971-976.
• Thompson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun. 2007;8:91-99.
• Matz H, Tur E. Vitiligo. Curr Probl Dermatol. 2007;35:78-102.
• Korsunskaya IM, Suvorova KN, Dvoryankova EV. Modern aspects of vitiligo pathogenesis. Dokl Biol Sci. 2003;388:38-40.
• Halder RM, Chappell JL. Vitiligo update. Semin Cutan Med Surg Jun 2009;28(2):86-92.
• Laddha NC, Dwivedi M, Begum R. Increased Tumor necrosis factor (TNF)-α and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo. PLoS One. 2012;7(12):e52298.
• Kotobuki Y, Tanemura A, Yang L, et al. Dysregulation of melanocyte function by Th17-related cytokines: significance of Th17 cell infiltration in autoimmune vitiligo vulgaris. Pigment Cell Melanoma Res. 2012;25(2):219-230.
• Singh RK, Lee KM, Vujkovic-Cvijin I, et al. The role of IL-17 in vitiligo: a review. Autoimmun Rev. 2016;15(4):397-404.
• Karagün E, Baysak S. Levels of TNF-α, IL-6, IL-17, IL-37 cytokines in patients with active vitiligo. Aging Male. 2020;23(5):1487-1492.
• Zapata-Salazar NA, Kubelis-Lopez DE, Salinas-Santander MA, et al. Association of rs4711998 of IL-17A, rs2275913 of IL-17A and rs763780 IL-17F gene polymorphisms with non-segmental vitiligo in a Mexican population. Arch Dermatol Res. 2022;12.
• Jadeja SD, Vaishnav J, Bharti AH, Begum R. Elevated x-box binding protein1 splicing and ınterleukin-17A expression are associated with active generalized vitiligo in gujarat population. Front Immunol. 2022;12:801724.
• Mohammed FN, Sayed Amr K, Abdel Raheem HM, et al. Study of interleukin-17 gene polymorphism and susceptibility to vitiligo in a sample of the Egyptian population. Journal of the Egyptian Women's Dermatologic Society. 2017;14(1):45-48.
• Granum B, Løvik M. The effect of particles on allergic immune responses. Toxicol Sci. 2002;65(1):7-17. Nakanishi K, Tsutsui H, Yoshimoto T. Importance of IL-18-induced super Th1 cells for the development of allergic inflammation. Allergol Int. 2010;59(2):137-141.
• Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423-474.
• Gangemi S, Merendino RA, Guarneri F, et al. Serum levels of interleukin-18 and s-ICAM-1 in patients affected by psoriasis: preliminary considerations. J Eur Acad Dermatol Venereol. 2003;17(1):42-46.
• Zhou J, Ling J, Wang Y, Shang J, Ping F. Cross-talk between interferon-gamma and interleukin-18 in melanogenesis. J Photochem Photobiol B. 2016;163:133-143.
• Westhoff LJ, Hughes SJ, Gill E, Walker T, Poole BD. Il-18 overproduction associated with NLRP1 single nucleotide polymorphisms linked to risk for vitiligo. International Journal of Clinical & Experimental Dermatology. 2021;6(2):1-4.