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...
Restricted use of T cell receptor (TCR) gene segments is characteristic of several induced autoimmune disease models. TCR sequences have previously been unavailable for pathogenic T cells which react with a defined autoantigen in a spontaneous autoimmune disease. The majority of T cell clones, derived from islets of NOD mice which spontaneously develop type I diabetes, react with insulin peptide B-(9-23). We have sequenced the ␣ and  chains of TCRs from these B-(9-23)-reactive T cell clones. No TCR  chain restriction was found. In contrast, the clones (10 of 13) used V␣13 coupled with one of two homologous J␣ segments (J␣45 or J␣34 in 8 of 13 clones). Furthermore, 9 of 10 of the V␣13 segments are a novel NOD sequence that we have tentatively termed V␣13.3. This dramatic ␣ chain restriction, similar to the  chain restriction of other autoimmune models, provides a target for diagnostics and immunomodulatory therapy.Type I diabetes mellitus, which develops spontaneously in man (1), the NOD mouse (2), and the BB rat, is considered a T cell-mediated autoimmune disorder. In the past 2 years, Wegmann and coworkers (3-5) have isolated CD4 ϩ T cells from islets of prediabetic NOD mice. T cell lines were established after stimulation with whole islets and were later discovered to react with insulin. Most (93%) of these insulin-reactive T cell clones react with an insulin B chain peptide consisting of amino acids 9-23. These T cells are present within islet lesions when the mice were first tested (4 weeks of age). They are pathogenic and rapidly lead to insulitis and diabetes when injected into young NOD mice (6). In addition, the same T cell clones can destroy transplanted human islets in an NOD͞scid mouse in vivo (7).Several autoimmune disorders have been linked to autoreactive T cells using T cell receptors (TCRs) with restricted variable chains. The best example of this restriction is experimental allergic encephalomyelitis associated with V8.2 and V␣2 in Lewis rats (8), and V8.2 and either V␣2 or V␣4 in B10.PL (9) and PL͞J mice (10). The J␣ segments share homology as well, with the
Technology has become available to cost-effectively analyze thousands of single nucleotide polymorphisms (SNPs). We recently confirmed by genotyping a small series of class I alleles and microsatellite markers that the extended haplotype HLA-A1-B8-DR3 (8.1 AH) at the major histocompatibility complex (MHC) is a common and conserved haplotype. To further evaluate the region of conservation of the DR3 haplotypes, we genotyped 31 8. M ore than 20 years ago, analysis of polymorphisms of complement genes, such as the 21-hydroxylase gene and alleles of class I and II major histocompatibility complex (MHC) genes, identified a number of MHC haplotypes that were termed "conserved extended haplotypes" or "ancestral haplotypes" (1-4). A Basque haplotype studied in U.S. French-Canadian populations with the HLA A30, Cw5, B18, BfF1, C4F, C4s°, DR3 haplotype was associated with diabetes susceptibility, and more recent studies have confirmed increased risk associated with this haplotype (5). The HLA-A1-B8-DR3 haplotype (8.1 AH) is one of the most common extended DR3 haplotypes, with a northernEuropean frequency of ϳ10%. The 8.1 AH consists of the HLA-A1, HLA-Cw7, HLA-B8, MICA-5.1, DR3, and DQ2 alleles (6) and has been sequenced by Stewart et al. (7). It has been associated with multiple immunological diseases, such as type 1 diabetes, celiac disease, systemic lupus erythematosus, common variable immunodeficiency, myasthenia gravis, and accelerated HIV disease (8 -10). However, a recent study has reported that the 8.1 AH is not more diabetogenic compared with other DR3 haplotypes (6).With the sequencing of the genome, the development of single nucleotide polymorphism (SNP) databases and haplotype maps, software to analyze haplotype blocks, and finally development of cost-effective large-scale SNP typing reagents, detailed multi-SNP analysis of the MHC region is now feasible. In this study, the analysis of multiple SNPs was necessary to describe the amount of conservation of the 8.1 AH or the proportion of alleles that were identical between 8.1 AHs. The basic scientific question we explored was how long and how conserved is the extended 8.1 AH? With our analysis of 656 SNPs of 31 8.1 AHs, we describe the 8.1 AH as having a remarkably long region (2.9 Mb) of Ͼ99.9% conservation. RESEARCH DESIGN AND METHODSIn the ongoing prospective Diabetes Autoimmunity Study of the Young (DAISY), participants (most with Caucasian and Hispanic ancestry) were HLA typed and stratified into groups by family history of type 1A diabetes. Subgroups of DAISY children were enrolled for prospective follow-up of development of anti-islet autoantibodies and diabetes. DNA samples from DAISY families, including children and parents with and without type 1 diabetes, were genotyped at the HLA-A, -B, -DRB1, and -DQB1 loci with sequence-specific oligonucleotide genotyping as previously described (11). The MICA microsatellite marker was genotyped using fluorescence-based methods as previously described (12). DNA from 45 of these families (143 individuals) was analy...
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