KİSTİK FİBROZİS HASTALARINDA FENOTİPİK CİDDİYETİ ETKİLEYEN GENLERİN VE İLİŞKİLİ YOLAKLARIN ARAŞTIRILMASI

Abstract

Cystic fibrosis, the most common autosomal recessive disease, is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. In addition to CFTR mutations, modifier genes and environmental factors play a role in disease severity. Interestingly there are patients with different clinical severity despite having the same CFTR mutation. The heterogeneity of disease severity among patients and the inability to establish genotype phenotype correlations make treatment approaches difficult. In this study two families with two siblings with Class-II mutations (F508del/F508del and F508del/G85E), one family with three siblings with Class-IV mutation (I1234V/I1234V) and three healthy individuals with no disease symptoms were included. Differential expressed genes and pathways were determined between affected siblings who have different disease severity (severe/mild) by using real-time PCR based cystic fibrosis PCR array. In severe siblings with Class-II mutation IL-17 (CXCL1, CXCL2), NF-kappa B (TNFRSF11A), TNF, cytokine cytokine receptor interaction, arachidonic acid metabolism, necroptosis, SNARE interaction (STX1A) and sodium reabsorption (SLC9A3R2) pathways were identified. AGE-RAGE, TLR pathways were determined only in Class IV severe siblings. As a result of analysis of all patients and comparison of them to control group; ICAM1, EZR, TNFRSF1A and HSP70 genes were found to be differentially expressed. In addition, a correlation was determined between differentially expressed genes in AGE-RAGE, cytokine cytokine receptor interaction, and insulin resistance pathways in patients and liver disease symptoms. As a result of this study, genes and pathways responsible from phenotypic severity among affected siblings carrying the same mutation were identified. The results will provide opportunity for development of novel target molecules for treatment of disease.