Kolşisin Direnci Olan Ailevi Akdeniz Ateşi Hastalarında İfadesi Değişen miRNA’ların İnflamasyon ve İlaç Direnci ile İlişkisinin Belirlenmesi

Abstract

Tümerdem, B. Ş., Investigation of the Differentially Expressed miRNA’s in terms of Their Role in Inflammation and Drug Resistance in Colchicine Resistant Familial Mediterranean Fever Patients, Hacettepe University Graduate School of Health Sciences Medical Biology Programme Master of Science Thesis, Ankara, 2022. Familial Mediterranean fever (FMF) is a monogenic systemic autoinflammatory disease that clinical heterogeneity observed. The most common treatment method for familial Mediterranean fever is daily colchicine usage. However, in 2-5% of patients, colchicine resistance is observed. It is thought that epigenetic factors may play a role in the development of it. There are studies showing that epigenetic mechanisms, especially microRNAs from non-coding RNAs, play a role in the development of drug resistance. For this reason, it was thought that the possible relationship of microRNAs whose expression is changed in colchicine resistant patients with drug resistance and inflammation should be evaluated. The miRNA 4.0 array and miRNA expression analysis previously performed by our group was reevaluated within the scope of the thesis; 25 miRNAs with at least 2-fold expression change were found between the colchicine resistant patient group and the colchicine sensitive patient group. From these miRNA’s the ones that are highly associated with drug resistance were validated by qRT-PCR in the patient group, miR-15b-5p and miR-183-5p found significantly decreased in colchicine resistant patients while the expression of miR-125a-5p was found to decrease insignificantly. Using bioinformatics tools, a list of genes associated with both inflammation and drug resistance was created, and possible target genes of microRNAs associated with drug resistance and inflammation were determined. It was shown that the expression of selected possible target genes NR3C1 and NFKB1 was increased in the same patient group in correlation with miRNAs. In the colchicine resistant cell line created during previous projects of our group, it was shown that expression of selected miRNAs and target genes showed a similar change with the patient group. The miRNAs whose expression is changed in colchicine resistant patients determined by this study have the potential to be a biomarker for the early diagnosis of colchicine resistance in the future.