Genetics of the HLA Region in the Prediction of Type 1 Diabetes
- 1.1k Downloads
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.
KeywordsType 1 diabetes Genetic risk HLA class II HLA class I HLA class III Risk prediction
This work was supported by National Institutes of Health R01 DK61722 (J.A.N.).
No potential conflicts of interest relevant to this article were reported.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 18.•• Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, Mychaleckyj JC, Todd JA, Bonella P, Fear AL, Lavant E, Louey A, Moonsamy P: HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families. Diabetes 2008, 57:1084–1092. This paper summarizes the analyses of HLA class II DR- and DQ-encoding genes on T1D risk in the T1DGC samples. PubMedCrossRefGoogle Scholar
- 42.• Varney MD, Valdes AM, Carlson JA, Noble JA, Tait BD, Bonella P, Lavant E, Fear AL, Louey A, Moonsamy P, Mychaleckyj JC, Erlich H: HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes 2010, 59:2055–2062. This paper summarizes the results of T1D association analyses of the HLA class II genes encoding the DP molecule in the T1DGC samples. PubMedCrossRefGoogle Scholar
- 43.Serreze DV, Holl TM, Marron MP, Graser RT, Johnson EA, Choisy-Rossi C, et al. MHC class II molecules play a role in the selection of autoreactive class I-restricted CD8 T cells that are essential contributors to type 1 diabetes development in nonobese diabetic mice. J Immunol. 2004;172:871–9.PubMedGoogle Scholar
- 45.Nakanishi K, Kobayashi T, Murase T, Naruse T, Nose Y, Inoko H. Human leukocyte antigen-A24 and -DQA1*0301 in Japanese insulin-dependent diabetes mellitus: independent contributions to susceptibility to the disease and additive contributions to acceleration of beta-cell destruction. J Clin Endocrinol Metab. 1999;84:3721–5.PubMedCrossRefGoogle Scholar
- 46.•• Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, Lane JA, Lavant E, Rappner R, Louey A, Concannon P, Mychaleckyj JC, Erlich HA: HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 2010, 59:2972–2979. This paper describes the results of T1D association for HLA class I A, B, and C genes from the T1DGC samples. PubMedCrossRefGoogle Scholar
- 60.Bossuyt P. In Evidence-based laboratory medicine: principles, practice, and outcomes Washington, DC, USA, AACC Press, 2007, p. 67–81.Google Scholar
- 62.Aly TA, Ide A, Humphrey K, Barker JM, Steck A, Erlich HA, Yu L, Miao D, Redondo MJ, McFann K, Roberts CM, Babu SR, Norris JM, Eisenbarth GS, Rewers MJ: Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes. J Autoimmun 25 2005, Suppl:40–45.Google Scholar
- 66.Petrone A, Bugawan TL, Mesturino CA, Nistico L, Galgani A, Giorgi G, et al. The distribution of HLA class II susceptible/protective haplotypes could partially explain the low incidence of type 1 diabetes in continental Italy (Lazio region). Tissue Antigens. 2001;58:385–94.PubMedCrossRefGoogle Scholar
- 67.Pugliese A, Dorman JS, Steenkiste A. The 13th International Histocompatibility Working Group for Type 1 Diabetes (T1D) Joint Report. In: Hanson JA, editor. 13th International Histocompatibility Workshop and Conference. Seattle: IHWG Press; 2007. p. 788–96.Google Scholar
- 70.Petrone A, Battelino T, Krzisnik C, Bugawan T, Erlich H, Di Mario U, et al. Similar incidence of type 1 diabetes in two ethnically different populations (Italy and Slovenia) is sustained by similar HLA susceptible/protective haplotype frequencies. Tissue Antigens. 2002;60:244–53.PubMedCrossRefGoogle Scholar