title: The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes.
abstract: OBJECTIVE
  The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades.
  
  
  METHODS
  Caucasoid subjects (n = 462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped.
  
  
  RESULTS
  Mean +/- SD age at diagnosis, 8.5 +/- 4.5 years, did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest-risk DRB1 genotype DR3,4 (2000-2005, 28% vs. 1950-1969, 79%; P < 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000-2005, 48% vs. 1950-1969, 20%; P = 0.0002). The frequency of the DRX,X genotype was low (<or=3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (P < 0.0001) and DR4,X (P < 0.0001) and DR3,X (P = 0.015) genotypes but not for DR3,4.
  
  
  CONCLUSIONS
  The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.
authors.affiliation: Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Spiros
authors.initials: S
authors.lastname: Fourlanos
authors.forename: Michael D
authors.initials: MD
authors.lastname: Varney
authors.forename: Brian D
authors.initials: BD
authors.lastname: Tait
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.forename: Margo C
authors.initials: MC
authors.lastname: Honeyman
authors.forename: Peter G
authors.initials: PG
authors.lastname: Colman
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D004777:Environment; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015994:Incidence; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D014739:Victoria / Q000453:epidemiology; D044465:White People
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains