Introduction
Cystic fibrosis (CF), which is one of the most common autosomal recessive diseases in Caucasian populations caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The gene encodes for an ion channel located in the apical membrane of epithelial cells which transports chloride ions and bicarbonate.1 To date, over 2000 mutations have been reported in the CFTR gene. Mutations have been classified into seven groups that affect the production of CFTR protein (Class IA and IB), its trafficking (Class II), its conductance (Class III and Class IV), its function (Class V) and its stability (Class VI)2. Although CF is characterized by chronic progressive lung disease it also affects sweat glands, liver, pancreas, upper airway, intestine and reproductive systems.3
Especially Pseudomonas aeruginosa and Staphlyococcus aureus cause chronic lung infection in patients and lung disease is the primary reason for mortality and morbidity in CF4,5. As a result of defective CFTR protein in the pancreas approximately 60-80% of patients have exocrine pancreatic insufficiency6,7. Additionally, dysfunction in the pancreas causes CF-related diabetes (CFRD)8. On the other hand, CFTR protein is necessary for the stability of mucus acidity and hydration in the intestine and regulation of bile secretion in the liver.9 Meconium ileus occurs in approximately 5-20%, CF liver disease (CFLD) occurs in 5%-10% of patients.9,10 Another affected system in CF is the reproductive system. CF patients with mild CFTR mutations have been shown to be associated with congenital bilateral absence of vas deferens (CBAVD).11,12
Since CF is described as a multisystem disorder it is difficult to establish genotype-phenotype correlation. Interestingly, some studies have found that patients with the same genotype demonstrated variable disease severity.13,14,15 Especially studies conducted on twins and siblings with the same CFTR mutation but different clinical symptoms, suggested that CF-related genes and genes that interact with CFTR protein may play a role in clinical heterogeneity.16,17 In recent years, there have been transcriptomic approaches in order to characterize phenotypic variability comparing CF patients to healthy controls or mild to severe CF patients with the same CFTR mutation.18,19 However, there is no transcriptomic study that includes mild and severe siblings from families where families share the same genetic origin. In the present study, we performed targeted transcriptomic analysis to identify differentially expressed genes and associated molecular pathways between mild and severe siblings.