Stepwise or Linear Decrease in Penetrance of Type 1 Diabetes With Lower-Risk HLA Genotypes Over the Past 40 Years

  1. the Type 1 Diabetes Genetics Consortium
  1. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
  1. Corresponding author: Andrea K. Steck, andrea.steck{at}
  1. A.K.S. and T.K.A. contributed equally to this study.


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.

RESEARCH DESIGN AND 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.


    • Received October 5, 2010.
    • Accepted December 30, 2010.

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