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. FEV(1) 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Cell Line
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Child
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Cystic Fibrosis / genetics*
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Cystic Fibrosis / pathology
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Cystic Fibrosis / physiopathology
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Female
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Gene Expression
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Gene Expression Regulation
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Genes, Reporter
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Genetic Association Studies
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Humans
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Luciferases, Renilla / biosynthesis
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Luciferases, Renilla / genetics
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Lung / pathology
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Lung / physiopathology
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Male
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Middle Aged
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Polymorphism, Single Nucleotide*
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Promoter Regions, Genetic
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / genetics*
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Receptors, Immunologic / metabolism
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Respiratory Function Tests
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Young Adult
Substances
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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Luciferases, Renilla
Grants and funding
Institut National de la Santé et de la Recherche Médicale (Inserm), Assistance Publique-Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie Paris (UPMC), Agence Nationale de la Recherche (ANR), Direction Générale de la santé (DGS), Association Vaincre La Mucoviscidose, Société française de la mucoviscidose, Chancellerie des Universités (Legs Poix), Association Agir Informer Contre la Mucoviscidose (AICM), GIS-Institut des Maladies Rares. JB was supported by Rennes CHU-Hospital and SFP2A fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.