Öz
Giriş: CTLA-4 (sitotoksik T-lenfosit ilişkili antijen 4) geni, immünoglobulin gen süper ailesinin bir üyesidir ve T hücrelerine inhibe edici bir sinyal ileten proteini kodlamaktadır. Son günlerde immün kontrol noktası olan CTLA-4 geni araştırılan genler arasındadır. Bu çalışmada amaç; CTLA-4 geninde oluşan çeşitli polimorfizmlerin, CTLA-4 geni ile benzer genlerin Otoimmün Tiroid Hastalığı (OTH) patogenezine katkıda bulunabileceğini in silico olarak değerlendirmektir.
Gereç ve Yöntem: Çalışmamızda CTLA-4 geni ile benzer genleri bulmak için GeneMania ve STRING veri tabanları, tek nükleotid polimorfizmlerini (SNP’leri) bulmak için Polyphen2, Exome Variant Server ve SIFT veritabanları, mikro RNA’ları tespit etmek için; miRDB ve miRWalk veritabanları kullanıldı.
Bulgular: Çalışmamızdan elde ettiğimiz verilere göre; FYN geninin OTH’nın patogenezine katkıda bulunabileceğini, CTLA-4 geniyle ilişkili (rs201778935, rs138279736, rs369567630 ve rs376038796) şüpheli SNP’lerin olduğunu tespit ettik.
Sonuç: Çalışmamızda 31 miRNA’nın mesajcı RNA’ların protein üretmesini düzenleyici rol üstlendiğinden, terapötik açıdan önemli olduğunu düşünmekteyiz. Biyoinformatik yöntemlerle değerlendirdiğimiz bu çalışma, ilerde laboratuvar ortamında uygulanarak, birçok hastalığın patogenezinin aydınlatılmasına katkıda bulunabileceğini düşünmekteyiz.
Anahtar Kelimeler
Kaynakça
- Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily CTLA-4. Nature 1987; 328: 267-70.
- He F, Zhou Y, Wang X, et al. Functional Polymorphisms of CTLA-4 associated with aggressive periodontitis in the Chinese Han population. Cell Physiol Biochem 2018; 50: 1178-85.
- Li L, Liu J, Qin S, Li R. Correlation between CTLA-4 genetic polymorphisms, its serum protein level and the susceptibility to recurrent spontaneous abortion: A case-control study. Medicine (Baltimore) 2018 ; 97: e12754.
- Yao L, Liu B, Jiang L, Zhou L, Liu X. Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children. Hematology 2019; 24: 123-8.
- Pistillo MP, Fontana V, Morabito A, et al. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma inter group study. Cancer Immunol Immunother 2019; 68: 97-07.
- Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166–82.
- Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007; 7: 95-06.
- Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996; 4: 535-43.
- Esensten HJ, Helou AY, Chopra G, Weiss A, Bluestone AJ. CD28 costimulation: from mechanism to therapy. Immunity 2016; 17: 973-88.
- Kristiansen OP, Larsen ZM. CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity. Genes Immun 2000; 1: 170-84.
- Douroudis K, Prans E, Uibo R. CTLA-4 promoter polymorphisms are associated with latent autoimmune diabetes in adults. Hum Immunol 2009; 70: 921-4.
- Hunt KA. A common CTLA-4 haplotype associated with coeliac disease. Eur J Hum Genet 2005; 13: 440-4.
- Shojaa M. Association between 318C/T polymorphism of the CTLA-4 gene and systemic lupus erythematosus in Iranian patients. Int J Rheum Dis 2017; 20: 2040-4.
- Online Mendelian Inheritance in Man. https://omim.org/. (Erişim Tarihi: 09.04.2020) .
- National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/. (Erişim Tarihi: 09.04.2020)
- NCBI-SNP. https://www.ncbi.nlm.nih.gov/snp/. (Erişim Tarihi: 09.04.2020)
- Franz M, Rodriguez H, Lopes C, et al. GeneMANIA update 2018. Nucleic Acids Res 2018; 46: 60-4.
- Mering VC, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 2003; 31: 258-61.
- Mutarelli M, Marwah V, Rispoli R, et al. A community-based resource for automatic exome variant-calling and annotation in Mendelian disorders. BMC Genomics 2014; 15: S5.
- Sim LN, Kumar P, Hu J, Henikoff S, Schneider G, Pauline C. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012: 40: 452-7.
- Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013; 76: 7-20.
- Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 2015; 28: 146-52.
- Dweep H, Sticht C, Pandey P, Gretz N. miRWalk database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 2011; 44: 839-47.
- Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol 1999; 162: 5813-20.
- Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39: 98-106.
- Piccirillo CA, Shevach EM. Naturally-occurring CD4 + CD25 + immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 2004; 16: 81-8.
- Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+) CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303-9.
- Chen K, Kolls JK. Interluekin-17A. Gene 2017; 30: 8-4.
- Kim CH. FOXP3 and its role in the immune system. Adv Exp Med Biol 2009; 665: 17-9.
- Ganesh BB, Bhattacharya A, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res 2011; 31: 721-31.
- Hu Y, Zhang L, Chen H, et al. Analysis of regulatory T cell subsets and their expression of helios and PD-1 in patients with hashimoto thyroiditis. Int J Endocrinol 2019; 2019: 5368473.
- Watanabe A, Inoue N, Watanabe M, et al. Increases of CD80 and CD86 Expression on peripheral blood cells and their gene polymorphisms in autoimmune thyroid disease. Immunol Invest 2020; 49: 191-203.
- Caio RDC, Quaio Jozélio F, Carvalho Clovis A, Bueno CS Amanda S. Autoimmune disease and multiple autoantibodies in 42 patients with RA Sopathies. Am J Med Genet A 2012; 158A: 1077-82.
- Li J, Zhou H. Fyn gene polymorphisms contribute to both trait and state anxieties in healthy Chinese-Han individuals. Psychiatr Genet 2012; 22: 312-3.
- Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspect Clin Res 2016; 7: 68-74.
Öz
Introduction: CTLA-4 (cytotoxic T-lymphocyte associated antigen-4) gene is a member of the immunoglobulin gene superfamily, encoding the protein that transmits an inhibiting signal to T cells. The CTLA-4 gene is an immune checkpoint among the genes being investigated nowadays. The aim of this study was to find various polymorphisms in the CTLA-4 gene may contribute to the pathogenesis of autoimmune thyroid disease (AITD) by investigating the genes that are similar to the CTLA-4 gene.
Material and Method: In our study, we used GeneMania and STRING databases to find similar genes with CTLA-4 gene, then we used Polyphen2, Exome Variant Server and SIFT databases to find single nucleotide polymorphisms (SNPs), miRDB and miRWalk databases were used to detect micro RNAs in the CTLA-4 gene. According to our results, we found that the FYN gene may contribute to the pathogenesis of AITD.
Results: We discovered SNPs (rs201778935, rs138279736, rs369567630 and rs376038796) that are associated with the CTLA-4 gene. In our study, we have thought that 31 miRNAs are therapeutically important, they play a regulatory role in the production of proteins by messenger RNAs.
Conclusion: We believe that this study, which we evaluated with bioinformatics methods, can contribute to the explanation of the pathogenesis of many disease by performing lab based experiments in the future.
Anahtar Kelimeler
Kaynakça
- Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily CTLA-4. Nature 1987; 328: 267-70.
- He F, Zhou Y, Wang X, et al. Functional Polymorphisms of CTLA-4 associated with aggressive periodontitis in the Chinese Han population. Cell Physiol Biochem 2018; 50: 1178-85.
- Li L, Liu J, Qin S, Li R. Correlation between CTLA-4 genetic polymorphisms, its serum protein level and the susceptibility to recurrent spontaneous abortion: A case-control study. Medicine (Baltimore) 2018 ; 97: e12754.
- Yao L, Liu B, Jiang L, Zhou L, Liu X. Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children. Hematology 2019; 24: 123-8.
- Pistillo MP, Fontana V, Morabito A, et al. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma inter group study. Cancer Immunol Immunother 2019; 68: 97-07.
- Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166–82.
- Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007; 7: 95-06.
- Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996; 4: 535-43.
- Esensten HJ, Helou AY, Chopra G, Weiss A, Bluestone AJ. CD28 costimulation: from mechanism to therapy. Immunity 2016; 17: 973-88.
- Kristiansen OP, Larsen ZM. CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity. Genes Immun 2000; 1: 170-84.
- Douroudis K, Prans E, Uibo R. CTLA-4 promoter polymorphisms are associated with latent autoimmune diabetes in adults. Hum Immunol 2009; 70: 921-4.
- Hunt KA. A common CTLA-4 haplotype associated with coeliac disease. Eur J Hum Genet 2005; 13: 440-4.
- Shojaa M. Association between 318C/T polymorphism of the CTLA-4 gene and systemic lupus erythematosus in Iranian patients. Int J Rheum Dis 2017; 20: 2040-4.
- Online Mendelian Inheritance in Man. https://omim.org/. (Erişim Tarihi: 09.04.2020) .
- National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/. (Erişim Tarihi: 09.04.2020)
- NCBI-SNP. https://www.ncbi.nlm.nih.gov/snp/. (Erişim Tarihi: 09.04.2020)
- Franz M, Rodriguez H, Lopes C, et al. GeneMANIA update 2018. Nucleic Acids Res 2018; 46: 60-4.
- Mering VC, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 2003; 31: 258-61.
- Mutarelli M, Marwah V, Rispoli R, et al. A community-based resource for automatic exome variant-calling and annotation in Mendelian disorders. BMC Genomics 2014; 15: S5.
- Sim LN, Kumar P, Hu J, Henikoff S, Schneider G, Pauline C. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012: 40: 452-7.
- Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013; 76: 7-20.
- Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 2015; 28: 146-52.
- Dweep H, Sticht C, Pandey P, Gretz N. miRWalk database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 2011; 44: 839-47.
- Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol 1999; 162: 5813-20.
- Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39: 98-106.
- Piccirillo CA, Shevach EM. Naturally-occurring CD4 + CD25 + immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 2004; 16: 81-8.
- Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+) CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303-9.
- Chen K, Kolls JK. Interluekin-17A. Gene 2017; 30: 8-4.
- Kim CH. FOXP3 and its role in the immune system. Adv Exp Med Biol 2009; 665: 17-9.
- Ganesh BB, Bhattacharya A, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res 2011; 31: 721-31.
- Hu Y, Zhang L, Chen H, et al. Analysis of regulatory T cell subsets and their expression of helios and PD-1 in patients with hashimoto thyroiditis. Int J Endocrinol 2019; 2019: 5368473.
- Watanabe A, Inoue N, Watanabe M, et al. Increases of CD80 and CD86 Expression on peripheral blood cells and their gene polymorphisms in autoimmune thyroid disease. Immunol Invest 2020; 49: 191-203.
- Caio RDC, Quaio Jozélio F, Carvalho Clovis A, Bueno CS Amanda S. Autoimmune disease and multiple autoantibodies in 42 patients with RA Sopathies. Am J Med Genet A 2012; 158A: 1077-82.
- Li J, Zhou H. Fyn gene polymorphisms contribute to both trait and state anxieties in healthy Chinese-Han individuals. Psychiatr Genet 2012; 22: 312-3.
- Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V, Bansal P. MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspect Clin Res 2016; 7: 68-74.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Konular | Sağlık Kurumları Yönetimi |
| Bölüm | Research Articles [en] Araştırma Makaleleri [tr] |
| Yazarlar | |
| Yayımlanma Tarihi | 21 Eylül 2020 |
| Yayımlandığı Sayı | Yıl 2020 Cilt: 1 Sayı: 3 |
Cited By
ANALYSIS OF CTLA 4 GENE +49A/G AND CT60 A/G POLYMORPHISMS IN ALOPECIA AREATA PATIENTS
Sabuncuoglu Serefeddin Health Sciences
https://doi.org/10.55895/sshs.1335300
|
|
|
|
|
|
|
|
Dergimiz; TR-Dizin ULAKBİM, ICI World of Journal's, Index Copernicus, Directory of Research Journals Indexing (DRJI), General Impact Factor, Google Scholar, Researchgate, WorldCat (OCLC), CrossRef (DOI), ROAD, ASOS İndeks, Türk Medline İndeks, Eurasian Scientific Journal Index (ESJI) ve Türkiye Atıf Dizini'nde indekslenmektedir.
EBSCO, DOAJ, OAJI, ProQuest dizinlerine müracaat yapılmış olup, değerlendirme aşamasındadır.
Makaleler "Çift-Kör Hakem Değerlendirmesi”nden geçmektedir.
Üniversitelerarası Kurul (ÜAK) Eşdeğerliği: Ulakbim TR Dizin'de olan dergilerde yayımlanan makale [10 PUAN] ve 1a, b, c hariç uluslararası indekslerde (1d) olan dergilerde yayımlanan makale [5 PUAN].
Note: Our journal is not WOS indexed and therefore is not classified as Q.
You can download Council of Higher Education (CoHG) [Yüksek Öğretim Kurumu (YÖK)] Criteria) decisions about predatory/questionable journals and the author's clarification text and journal charge policy from your browser. About predatory/questionable journals and journal charge policy
Not: Dergimiz WOS indeksli değildir ve bu nedenle Q sınıflamasına dahil değildir.
Yağmacı/şüpheli dergilerle ilgili Yüksek Öğretim Kurumu (YÖK) kararları ve yazar açıklama metni ile dergi ücret politikası: Yağmacı/Şaibeli Dergiler ve Dergi Ücret Politikası