The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

  1. Spiros Fourlanos, FRACP, PHD1,2,
  2. Michael D. Varney, PHD3,
  3. Brian D. Tait, PHD3,
  4. Grant Morahan, PHD4,
  5. Margo C. Honeyman, PHD1,
  6. Peter G. Colman, MD, FRACP2 and
  7. Leonard C. Harrison, MD, FRACP, FRCPA, DSC1
  1. 1Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. 2Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  3. 3Victorian Transplantation and Immunogenetics Service, Parkville, Victoria, Australia
  4. 4Western Australian Institute for Medical Research, Perth, Australia
  1. Corresponding author: Leonard C. Harrison, harrison{at}


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.

RESEARCH DESIGN AND 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 (≤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.


  • Published ahead of print at on 16 May 2008.

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    • Received January 31, 2008.
    • Accepted May 8, 2008.
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  1. Diabetes Care vol. 31 no. 8 1546-1549
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