CXCL10 EKSPRESYONUNUN DÜZENLENMESİ VE CXCL10 DNA DİZİ VARYASYONU VE HASTALIK İLİŞKİLERİNİN İNCELENMESİ

Abstract

Amaç: Kemokin proteinlerinin, inflamasyon ve bağışıklıkta önemli rolleri vardır. Kemokinler, kemokin proteinleri ailesinin bir üyesi olup uygun kemokin reseptörlerini eksprese eden hücrelerde kemotaktik aktivite üreterek lökosit trafiğinde önemli bir rol oynarlar. CXCL10, CXC kemokin ailesinin bir üyesidir ve CXCR3 reseptörüne bağlanarak kemotaksi, apoptoz, hücre büyümesi, yeni damar oluşumu gibi biyolojik olaylarda etkili olur. CXCL10, otoimmün bozukluklar, transplantasyon, bulaşıcı hastalıklar ve kanser gibi farklı hastalık gruplarında etkileri olması dolayısıyla pleiotropiktir. Çalışmamızda CXCL10’un çeşitli hastalıkların patogenezi üzerindeki potansiyel rolünü değerlendirmek amaçlanmıştır. Gereç ve Yöntemler: CXCL10 ekspresyonunun eQTL etkileri ve mikroRNA’ların (miRNA’lar); birlikte düzenlenmiş gen kümeleri açısından düzenlenmesi incelendi. Gen-protein ve yolak etkileşimlerinin incelenmesi için STRING/GeneMANIA/KEGG PATHWAY/GeneCards; CXCL102’yi hedefleyen miRNA’ların tespiti için TargetScan/miRDB; CXCL10’u hedeflemek için Blood eQTL Tarayıcı / BIOS / mQTLdb; CXCL10 ve miRNA bölgesi tek nükleotid polimorfizmleri (SNP)’nin hastalıklarla olan ilişkisinin incelenmesi için GRASP ve GWAS, gen zenginleştirme analizi için ise GSEA/MSigDB veri tabanları kullanıldı. Bulgular: Birlikte eksprese edilen genler için, GSEA/MSigDB veri tabanında yapılan gen seti zenginleştirme analizi sonucunda, immün yanıt ve inflamatuar yanıtta yer alan genler, interferon ve düzenleyici T hücrelerine yanıtta yer alan genler, ve ayrıca meme ve prostat kanserlerinde yer alan genler ile gen setinin genişletilmesi önerildi (FDR<1E-50). CO-Düzenleme Veritabanı (CORD), CXCL10 çevresinde yer alan beş ek CXCL geni de dahil olmak üzere, yapısal olarak birlikte eksprese edilen 182 gen (5 kat eşikte) tanımladı. Birlikte eksprese edilen gen seti, herhangi bir miRNA’nın ortak hedefleri için zenginleşmeye sahip değildi. Çalışmamızda CXCL10’u hedefleyen miRNA’lar seçildi ve diğer hedef genleri belirlemek için de TargetScan programı kullanıldı. Böylece 80 miRNA belirlendi ve her bir miRNA’nın hedefleri aynı GSEA analizine tabi tutuldu. GWAS veri tabanlarındaki her bir miRNA gen bölgesi için SNP’lerin hastalıklar ile ilişkileri incelendi ve bu inceleme sonucunda Romatoid artrit, Ankilozan spondilit, Crohn Hastalığı, Psoriasis gibi otoimmün hastalıklar, Multipl Skleroz, Tip 1 diyabet, Miyastenia gravis ve alerji/astım gibi hastalıklar ile ilişki tespit edildi (P<1E- 04). CXCL10 içindeki SNP’ler için ise herhangi bir GWAS ilişkisi bulunmadı, ancak CXCL10 için kanda eQTL/meQTL olarak hareket eden SNP’lerin, uzun ömür, yaşlanma, inflamatuar barsak hastalığı (IBD) ve meme kanseri ile GWAS ilişkileri tespit edildi (P<1E-04). Çalışmamızda miRNA aracılı CXCL10 ekspresyonu için güçlü kanıtlar elde edilememiş olsa da, miRNA’ların yakınındaki varyantlar, inflamatuar ve immün bozukluklarla güçlü genetik ilişkiler gösterdi. Sonuç: CXCL10’un inflamasyon, otoimmünite ve muhtemelen kanserde oynadığı rolün transplantasyondan daha güçlü olduğu sonucuna vardık.

Keywords

• Genler
• hastalık ilişkileri
• otoimmün hastalıklar
• biyoinformatik
• CXCL10

REGULATION OF THE CXCL10 EXPRESSION AND INVESTIGATION OF THE RELATIONSHIPS OF THE CXCL10 DNA SEQUENCE VARIATION AND DISEASE

Abstract

Objective: Chemokine proteins are significantly effective in inflammation and immunity. Chemokines are from the family of the chemokine proteins and they organise the leukocyte trafficking through the formation of chemotactic activity in the cells that express the appropriate chemokine receptors. CXCL10 is involved in the CXC chemokine family and is effective in biological events such as chemotaxis, apoptosis, cell growth, and angiostasis through the attachment to the CXCR3 receptor. CXCL10 is pleiotropic due to its effects on different disease groups such as autoimmune disorders, transplantation, infectious diseases, and cancer. The aim of this study was to assess the potential role of CXCL10 on the pathogenesis of various diseases. Material and methods: The eQTL effects of CXCL10 expression and the regulation of microRNAs (miRNAs) in terms of co-regulated gene clusters were examined. The STRING/GeneMANIA/KEGG PATHWAY/GeneCards was used for the investigation of the gene-protein and pathway interactions; for the detection of miRNA targeting CXCL102, TargetScan/ miRDB was used; for the investigation of the association of CXCL10 and miRNA region single nucleotide polymorphisms (SNP) with the diseases, GRASP and GWAS were used; GSEA/MSigDB database was used for gene enrichment analysis Results: Both the GSEA/MSigDB tool and the gene set enrichment analysis recommended the use of the enriched forms of the genes involved in breast and prostate cancers and in response to inflammation, and to interferon and regulatory T cells (FDR<1E-50). 182 genes (at a 5-fold threshold) that are structurally co-expressed with five additional CXCL genes close to CXCL10 were identified with the use of the CO-Regulation database (CORD. No enrichment was detected for the common targets of any miRNA in the co-expressed gene sets. The CXCL10 targeting miRNAs were selected, and the TargetScan program was used to identify other target genes in our study. Thus, 80 miRNAs were identified, and the same GSEA analysis was performed for each miRNA target. The association of SNPs with the diseases was investigated for the gene region of each miRNA in the GWAS databases, and an association was detected with the autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis, and with multiple sclerosis, Type 1 diabetes, myasthenia gravis, and allergy/asthma (P<1E-04). For SNPs in CXCL10, no GWAS associations were found; however, SNPs acting as eQTL/ meQTL in the blood for CXCL10 had GWAS associations with longevity, aging, inflammatory bowel disease (IBD), and breast cancer (P<1E-04). Although we found no strong evidence for miRNA-mediated CXCL10 expression in our study, strong genetic associations were found associated with inflammatory and immune disorders in the miRNAs neighboring variants. Conclusion: In conclusion, we suggest that there is a stronger role of CXCL10 in inflammation, autoimmunity, and possibly cancer than its role in transplantation.

Keywords

• Genes
• disease relationships
• autoimmune diseases
• bioinformatics
• CXCL10

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