title: Circulating concentrations of soluble receptor for AGE are associated with age and AGER gene polymorphisms in children with newly diagnosed type 1 diabetes.
abstract: OBJECTIVE
  We analyzed the relationship among soluble receptor for advanced glycation end products (sRAGEs), the clinical phenotype, HLA genotype, and risk-associated single nucleotide polymorphisms (SNPs) in the AGER gene in a large population of Finnish children with newly diagnosed type 1 diabetes.
  
  
  METHODS
  Samples from 2,115 clinically phenotyped children <15 years of age in whom type 1 diabetes was diagnosed and 316 control subjects were analyzed for sRAGEs. Three SNPs of AGER, previously associated with HLA-DR/DQ haplotype independent diabetes risk (rs2070600, rs9469089, and rs17493811), were analyzed in 1,390 affected subjects.
  
  
  RESULTS
  Children with type 1 diabetes and control subjects had similar sRAGE concentrations (1,171 vs. 1,153 pg/mL, P = 0.48). There was a correlation between age at diagnosis and serum sRAGE concentrations (r = 0.10, P < 0.001) among the patients but not among the control subjects. Children <2 years of age had the lowest concentrations in the diabetic population (1,027 vs. 1,181 pg/mL, P < 0.001) and the highest among the control subjects (1,329 vs. 1,140 pg/mL, P = 0.04). Ketoacidosis at diagnosis was associated with reduced concentrations (1,086 vs. 1,190 pg/mL, P < 0.001). HLA DR3/DR4 heterozygosity and the DR3 allele were associated with reduced sRAGE concentrations. The predisposing AA genotype of rs2070600 was associated with decreased sRAGE concentrations, while the protective CC genotype of rs9469089 was linked to increased concentrations.
  
  
  CONCLUSIONS
  Age and AGER polymorphisms are associated with the circulating sRAGE concentration among children with type 1 diabetes. The observations of reduced sRAGE concentrations in young children, in those with ketoacidosis, and in carriers of the high-risk HLA DR3/DR4 genotype suggest that decreased sRAGE concentration reflects a more aggressive disease phenotype.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandDiabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Kirsi M
authors.initials: KM
authors.lastname: Salonen
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandDiabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Samppa J
authors.initials: SJ
authors.lastname: Ryhänen
authors.affiliation: Mater Research, Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandDiabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Härkönen
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, FinlandDepartment of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Laine
authors.affiliation: Diabetes and Obesity Research Program, University of Helsinki, Helsinki, FinlandFolkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, FinlandDivision of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, FinlandBaker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandDiabetes and Obesity Research Program, University of Helsinki, Helsinki, FinlandFolkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, FinlandDepartment of Pediatrics, Tampere University Hospital, Tampere, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005838:Genotype; D017127:Glycation End Products, Advanced / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D017127:Glycation End Products, Advanced; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic