Serum-Based Proteomics Profiling in Adult Patients with Cystic Fibrosis

Hicham Benabdelkamel,Ibrahim O Alanazi,Imran Nizami,Assim A Alfadda,Afshan Masood,Hanadi Alamri,Majed Dasouki,Meshail Okla,Mai Abdel Jabar,Anas M Abdel Rahman

doi:10.3390/ijms21197415

Abstract

Cystic fibrosis (CF), the most common lethal autosomal recessive disorder among Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel gene. Despite significant advances in the management of CF patients, novel disease-related biomarkers and therapies must be identified. We performed serum proteomics profiling in CF patients (n = 28) and healthy subjects (n = 10) using the 2D-DIGE MALDI-TOF proteomic approach. Out of a total of 198 proteins identified, 134 showed a statistically significant difference in abundance and a 1.5-fold change (ANOVA, p < 0.05), including 80 proteins with increased abundance and 54 proteins with decreased abundance in CF patients. A multiple reaction monitoring-mass spectrometry analysis of six differentially expressed proteins identified by a proteomic approach (DIGE-MALD-MS) showed a significant increase in C3 and CP proteins and a decrease in APOA1, Complement C1, Hp, and RBP4proteins compared with healthy controls. Fifteen proteins were identified as potential biomarkers for CF diagnosis. An ingenuity pathway analysis of the differentially regulated proteins indicates that the central nodes dysregulated in CF subjects involve pro-inflammatory cytokines, ERK1/2, and P38 MAPK, which are primarily involved in catalytic activities and metabolic processes. The involved canonical pathways include those related to FXR/RXR, LXR/RXR, acute phase response, IL12, nitric oxide, and reactive oxygen species in macrophages. Our data support the current efforts toward augmenting protease inhibitors in patients with CF. Perturbations in lipid and vitamin metabolism frequently observed in CF patients may be partly due to abnormalities in their transport mechanism.

Highlights

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that causes significant morbidity and mortality, mainly in the Caucasian population [1,2,3]
We aimed to perform quantitative serum proteomics analyses in CF patients using the two-dimensional difference in gel electrophoresis (2D-Differential in-gel electrophoresis (DIGE)) coupled with high-resolution mass spectrometry (MS) and to assess the differences compared with healthy subjects
Eight different CFTR mutations were identified, which represent 46.5% of all CFTR alleles reported in the Saudi Arabian patients with CF [19]

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that causes significant morbidity and mortality, mainly in the Caucasian population [1,2,3]. It affects 1 in 2000–3000 newborns in the EU and 1 in 3500 in the USA [3]. Mutations cause CF in the CF transmembrane conductance regulator (CFTR) gene [5,6], which is a PKA-regulated chloride channel expressed in the apical membrane of the epithelial cells regulating secretion and absorption processes in tissues such as the lungs, pancreas, intestine, and kidneys, where it regulates water and salt balance [1,7,8]. Disruption of normal ion homeostasis in the airway causes mucoviscidosis (thick mucus), which makes the lungs more vulnerable to persistent and recurrent infections [5,6,12]

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