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

Abstract

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 DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated "DR3") and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; 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 DRB1*15:01-DQA1*01:02-DQB1*06:02 (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, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (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.

Figure 1

Schematic map of the HLA region showing genes reported to be associated with type 1 diabetes (T1D). Map positions to chromosome 6 are from HapMap Rel 28 NCBI B36. Asterisk (*) indicates the signal maps to a 500-kb region between the UBD gene and the MAS1L gene also comprising several other genes [58].

Figure 2

Forest plot showing study-specific estimates for the association between the HLA class II DR3/DR4 genotype and type 1 diabetes (T1D). DR3 = DRB1*03:01-DQA1*05:01-DQB1*02. DR4 = DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02). Total sample size = 5130 T1D cases and 6366 controls from 14 studies. P = 6 × 10[−293] (fixed effects meta-analysis). No significant interstudy heterogeneity was observed: I² = 13% p(Cochran’s Q) < 0.3 (see [55] for a description of the meta-analysis methods). Case and control genotype counts were derived from the following published studies: Sardinia [65] T1D = 1052, controls = 1917; Italy [66] T1D = 134, controls = 128; USA-HBDI collection [9] T1D = 283, controls = 199; USA-DAISY collection [6263] T1D = 837, controls = 115; United Kingdom [10] T1D = 753, controls = 753; Sweden [67] T1D = 628, controls = 501; Finland [68] T1D = 622, controls = 622; Hungary [69] T1D = 149, controls = 177; Slovenia [70] T1D = 171, controls = 117; Turkey [71] T1D = 178, controls = 248; Hong Kong [72] T1D = 76, controls = 250; Singapore [71, 73] T1D = 73, controls = 80; Philippines [74] T1D = 90, controls 191; USA Mexican American [75] T1D = 84, controls = 68; For the non-Caucasian studies the control genotype counts were zero, the frequency in controls was estimated as ½ × number of controls. See Thomson et al. [12] for details on study selection criteria. DAISY—Diabetes Autoimmunity in the Young; HBDI—Human Biological Data Interchange.