A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease

Z. L. Awdeh, Edmond J. Yunis, Mark J. Audeh, Dolores Fici, Alberto Pugliese, Charles E. Larsen, Chester A. Alper

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


We had earlier hypothesized, if parents originated from previously isolated populations that had selected against different critical susceptibility genes for a polygenic disease, their offspring could have a greater risk of that disease than either parent. We therefore studied parents of patients with type 1 diabetes (T1D). We found that parents who transmitted HLA-DR3 to HLA-DR3/DR4 patients had different HLA-A allele frequencies on the non-transmitted HLA haplotype than HLA-DR4-transmitters. HLA-DR3-positive parents also had different insulin (INS) gene allele frequencies than HLA-DR4-positive parents. Parent pairs of patients had greater self-reported ethnicity disparity than parent pairs in control families. Although there was an excess of HLA-DR3/DR4 heterozygotes among type 1 diabetes patients, there were significantly fewer HLA-DR3/DR4 heterozygous parents of patients than expected. These findings are consistent with HLA-DR and INS VNTR alleles marking both disease susceptibility and separate Caucasian parental subpopulations. Our hypothesis thus explains some seemingly disconnected puzzling phenomena, including (1) the rising world-wide incidence of T1D, (2) the excess of HLA-DR3/DR4 heterozygotes among patients, (3) the changing frequency of HLA-DR3/DR4 heterozygotes and of susceptibility alleles in general in patients over the past several decades, and (4) the association of INS alleles with specific HLA-DR alleles in patients with T1D.

Original languageEnglish (US)
Pages (from-to)174-181
Number of pages8
JournalJournal of Autoimmunity
Issue number3
StatePublished - Nov 2006


  • Excess heterozygosity
  • Rising incidence of type 1 diabetes
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy


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