AGER -429T/C Is Associated with an Increased Lung Disease Severity in Cystic Fibrosis

Julie Beucher,Céline Muselet-Charlier,Pierre-François Busson,Harriet Corvol,Annick Clement,Pierre-Yves Boëlle,Anthony W.I Lo

doi:10.1371/journal.pone.0041913

Abstract

The clinical course of cystic fibrosis (CF) varies between patients bearing identical CFTR mutations, suggesting the involvement of modifier genes. We assessed the association of lung disease severity with the variant AGER -429 T/C, coding for RAGE, a pro-inflammatory protein, in CF patients from the French CF Gene Modifier Study. We analyzed the lung function of 967 CF patients p.Phe508del homozygous. FEV1 was analyzed as CF-specific percentile adjusted on age, height and mortality. AGER -429T/C polymorphism was genotyped and its function was evaluated in vitro by measurement of the luciferase activity. AGER -429 minor allele (C) was associated with poorer lung function (p = 0.03). In vitro, the promoter activity was higher in cells transfected with AGER -429C compared to cells transfected with the AGER -429T allele (p = 0.016 in BEAS-2B cells). AGER seems to be a modifier gene of lung disease severity in CF, and could be an interesting biomarker of CF airway inflammation. The functional promoter AGER -429C variant is associated with an increased RAGE expression that can lead to an increased lung inflammation and a more severe lung disease.

Highlights

IntroductionCystic fibrosis (CF) is the most common severe autosomal recessive genetic disease in Caucasians caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene
Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disease in Caucasians caused by mutations in the CFTR gene
This study demonstrated that AGER could be a modifier gene of lung disease severity in CF

Summary

Introduction

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disease in Caucasians caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. RAGE is a member of the cell surface receptor immunoglobulin superfamily. It is a multiligand receptor with a short cytosolic domain and a large extra cellular region containing 3 immunoglobulin-like-domains (V, C1, C2 domains). These domains co-ordinately interact and bind with different ligands, leading to the activation of several proinflammatory signalling pathways [3]. RAGE has been shown to be either increased or decreased [2,7,8]. Increased levels of RAGE have been observed in the alveolar walls of patients with chronic obstructive pulmonary disease (COPD) compared to controls [8]. Loss of RAGE has been incriminated in idiopathic pulmonary fibrosis pathogenesis [7]

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Results

Conclusion