Genetics of the HLA region in the prediction of type 1 diabetes.

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40-50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB103:01-DQA105:01-DQB102:01 (abbreviated "DR3") and DRB104:01/02/04/05/08-DQA103:01-DQB103:02/04 (or DQB102; abbreviated "DR4"). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7-20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12-7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB115:01-DQA101:02-DQB106:02 (abbreviated "DR2"; OR = 0.03; 95% CI, 0.01-0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB104:02, DPB103:01, and DPB102:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B39:06 (OR =10.31; 95% CI, 4.21-25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.