title: The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro.
abstract: BACKGROUND
  Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model.
  
  
  METHODS
  Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified.
  
  
  RESULTS
  Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production.
  
  
  CONCLUSIONS
  This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism.
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Miller
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Henry
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Hodge
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Kheirallah
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Charlotte K
authors.initials: CK
authors.lastname: Billington
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Rimington
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Sangita K
authors.initials: SK
authors.lastname: Bhaker
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Merid
authors.affiliation: Department of Biology, University of York, York, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Swan
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gowland
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ceri E
authors.initials: CE
authors.lastname: Stewart
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Bolton
authors.affiliation: Pfizer Worldwide Research & Development, Cambridge, Massachusetts, United States of America.
authors.forename: Iain
authors.initials: I
authors.lastname: Kilty
authors.affiliation: Pfizer Worldwide Research & Development, Cambridge, United Kingdom.
authors.forename: Anders
authors.initials: A
authors.lastname: Malarstig
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Parker
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
authors.affiliation: Institute for Lung Health, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wardlaw
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Sayers
mesh_terms: D000483:Alleles; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012907:Smoking; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; C000593871:AGER protein, human