Although HLA-DR3/4 genotype confers extremely high risk, there is a spectrum of risk associated with HLA-DR/DQ genotype-from increased, to neutral, to protective. For instance, the HLA-DQA1*0102, DQB1*0602 haplotype confers dominant protection from type 1 diabetes, even in the presence of islet autoantibodies. However, while the incidence of type 1 diabetes is increasing, the percentage of patients carrying the high risk HLA-DR3/4 genotype is decreasing. These temporal changes in HLA genotypes suggest increased environtmental pressure with higher disease progression rate in individuals with lower risk HLA genotypes and/or contribution of other non-HLA class II alleles or non-HLA-related alleles to type I diabetes risk.
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