title: Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years.
abstract: OBJECTIVE
  The objective of this study was to test if the proportion of new-onset diabetic subjects with the HLA-DR3/4-DQB1*0302 genotype is decreasing over time.
  
  
  METHODS
  We analyzed HLA class II genotype frequencies over time in two large populations with type 1 diabetes diagnosed at ≤18 years of age. There were 4,075 subjects from the Type 1 Diabetes Genetics Consortium (T1DGC) and 1,675 subjects from the Barbara Davis Center (BDC).
  
  
  RESULTS
  Both T1DGC and BDC cohorts showed a decrease of the highest-risk HLA-DR3/4-DQB1*0302 genotype over time. This decrease was greatest over time in T1DGC subjects with age of onset ≤5 years (P = 0.004) and onset between ages 6 and 10 years (P = 0.002). The overall percent of HLA-DR3/4-DQB1*0302 was greater in the T1DGC population compared with the BDC population. There was an increased percent over time of other HLA genotypes without HLA-DR3 or -DR4 in T1DGC new onsets (P = 0.003), and the trend was similar in BDC subjects (P = 0.08). Analyzing time trend, there appears to be a large stepwise decrease in percent DR3/4 in the 1980s in T1DGC subjects with onset age <5 years (P = 0.0001).
  
  
  CONCLUSIONS
  The change in frequency of multiple different genotypes and a possible stepwise decrease in percent DR3/4 suggest a change in genetic risk factors and environmental determinants of type 1 diabetes. Larger studies are needed to confirm the changing pattern of genetic risk because a stepwise change may have direct bearing on defining critical environmental determinants of type 1 diabetes.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA. andrea.steck@ucdenver.edu
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Steck
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Armstrong
authors.forename: Sunanda R
authors.initials: SR
authors.lastname: Babu
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015803:HLA-DR3 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015994:Incidence; D008297:Male; D019683:Penetrance; D012307:Risk Factors
chemical_list: D015803:HLA-DR3 Antigen