Article

Extreme genetic risk for type 1A diabetes.

Barbara Davis Center for Childhood Diabetes and Human Medical Genetics Program, University Colorado Health Sciences Center, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2006; 103(38):14074-9. DOI: 10.1073/pnas.0606349103
Source: PubMed

ABSTRACT Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ 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 DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-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 DR3/4-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 DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-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-DR/DQ 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.

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    • "However, HLA genotyping in firstdegree relatives of T1D probands can be useful. Aly et al. (2006) reported that risk for islet autoimmunity drastically increased in DR3/4- DQ2/DQ8 siblings who shared both HLA haplotypes identical by descent with their diabetic proband sibling (63% by age 7, and 85% by age 15) as compared with siblings who did not share both HLA haplotypes with their diabetic proband siblings (Fig. 3). These data indicate that HLA genotyping at birth may identify individuals at very high risk of developing T1D, before the occurrence of clear signs of humoral autoimmunity and eventually overt disease. "
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    ABSTRACT: Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated β-cell injury and, in turn, preserving β-cell function in type 1 diabetes mellitus.
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    • "Using the candidate gene approach, association studies provided evidence for the first two susceptibility loci, the HLA region and the insulin gene (INS) locus. These two loci only contribute a portion of the familial clustering (40-50% for HLA and 10% for INS), suggesting the existence of additional loci (Aly et al 2006, Jahromi & Eisenbarth 2006 & 2007, Barrett et al 2009 "
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    • "Extreme T1D risk (up to 50%) will be present in children with the HLA DRB1*03,*04; DQB1*0302 genotype born into a family with two or more affected family members (Bonifacio et al., 2004). Similar extreme risks were reported for children who are HLA DRB1*03,*04; DQB1*0302 and are identical by descent to their affected sibling at these loci (Aly et al., 2006). "
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