Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR͞DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3͞4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3͞4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3͞4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P ؍ 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3͞4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3͞4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR͞DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.haplotype ͉ human leukocyte antigen ͉ major histocompatibility complex A large body of evidence indicates that type 1A diabetes (T1D) is an autoimmune disorder with important genetic determinants, and it has become one of the most intensively studied complex genetic disorders (1-3). The major histocompatibility complex (MHC) is reported to account for Ϸ40% of the familial aggregation of T1D (4, 5). The HLA-DR and -DQ genes (linked HLA genes in the class II region of the MHC) are well established as being associated with risk for T1D. Although studies have implicated loci other than the HLA-DR and -DQ loci (i.e., HLA-DPB1, HLA-A, HLA-B, and various non-HLA genes) with diabetes risk and earlier age of onset, no loci with contribution to risk equivalent to that of the HLA-DR and -DQ alleles have been identified (6-10).The insulin, PTPN22, and CTLA4 genes are non-HLA diabetes-susceptibility loci with allelic odds ratios of 1.9, 1.7, and 1.2, respectively (11-14). However, even in combination with HLA alleles, none of these identified loci confer a risk Ͼ25% in prospective studies. Nevertheless, a remaining fundamental question is whether there are genetic polymorphisms other than the HLA-DR and -DQ alleles that confer major risk for T1D. If such loci existed, they could be linked to the MHC and would thus be ''hidden'' in most linkage studies by the dramatic influence of the HLA-DR and -DQ alleles.Haplotypes are defined by sets of closely linked genetic variants making chromosom...
Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic beta-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway.
(DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-bydescent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes. RESEARCH DESIGN AND METHODS-We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium.RESULTS-We found evidence for an association with type 1A diabetes (rs1233478, P ϭ 1.6 ϫ 10 Ϫ23 , allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P ϭ 1.4 ϫ 10 Ϫ12 ) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P ϭ 0.01). CONCLUSIONS-Polymorphisms
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