Genetic risk for T1D overlaps with AIT, CD, and AD. Disease risk is associated with organ-specific autoantibodies, which can be used to screen subjects with T1D.

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.

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...

OBJECTIVE -The objective of this study was to determine whether earlier diagnosis of diabetes in prospectively followed autoantibody-positive children lowered onset morbidity and improved the clinical course after diagnosis. RESEARCH DESIGN AND METHODS -The Diabetes Autoimmunity Study in theYoung (DAISY) follows genetically at-risk children for the development of diabetes. Increased genetic risk is identified by family history of type 1 diabetes or expression of diabetes-associated HLA genotypes. Of the 2,140 prospectively followed children, 112 have developed islet autoantibodies and 30 have progressed to diabetes. Diabetes onset characteristics and early clinical course of these 30 children followed to diabetes were compared with those of 101 age-and sex-matched children concurrently diagnosed with diabetes in the community.RESULTS -Pre-diabetic children followed to diabetes were less often hospitalized than the community cases (3.3 vs. 44%; P Ͻ 0.0001). They had a lower mean HbA 1c at onset (7.2 vs. 10.9%; P Ͻ 0.0001) and 1 month after diagnosis (6.9 vs. 8.6%; P Ͻ 0.0001) but not after 6 months of diabetes. The mean insulin dose was lower in the DAISY group at 1 (0.30 vs. 0.51 U ⅐ kg Ϫ1 ⅐ day Ϫ1; P ϭ 0.003), 6 (0.37 vs. 0.58; P ϭ 0.001), and 12 months (0.57 vs. 0.72; P ϭ 0.03). There was no difference in growth parameters between the two groups. Comparisons limited to children with a family history of type 1 diabetes in both groups showed a similar pattern.CONCLUSIONS -Childhood type 1 diabetes diagnosed through a screening and follow-up program has a less severe onset and a milder clinical course in the first year after diagnosis. Diabetes Care 27:1399 -1404, 2004T ype 1 diabetes affects ϳ15-30 million people globally and 1.4 million in the U.S. (1,2). The incidence is increasing by 3-5% per year (3,4), especially among young children (5-9). Type 1 diabetes is responsible for significant morbidity, premature mortality (10), and financial burden (11). The disease usually is preceded by a preclinical period lasting months to years. Pre-diabetes can often be detected by the presence of autoantibodies to islet antigens such as GAD65, insulin, and IA-2 that are highly predictive of type 1 diabetes risk in children with (12) and without (13) a first-degree type 1 diabetic relative.In the absence of effective prevention, screening for pre-diabetes is currently not recommended outside of research studies. To date, interventions applied after the development of islet autoantibodies have been unsuccessful in slowing progression to diabetes (14,15). Several ongoing cohort studies (16 -19) follow high-risk children from birth to determine environmental triggers of type 1 diabetes. Interventions based on avoidance of these triggers before the onset of autoimmunity could be effective in preventing type 1 diabetes.One of these projects, Diabetes Autoimmunity Study in the Young (DAISY) (16,19), intensively follows two groups of children at increased risk for the development of diabetes: young first-degree relatives and infa...