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. 2013 May;36(5):1181-5.
doi: 10.2337/dc12-1712. Epub 2012 Dec 28.

Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome

Rachel J Aitken  1 , Kay L Mehers, Alistair J Williams, Jamie Brown, Polly J Bingley, Reinhard W Holl, Tilman R Rohrer, Edith Schober, Majedah M Abdul-Rasoul, Julian P H Shield, Kathleen M Gillespie
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Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome

Rachel J Aitken et al. Diabetes Care. 2013 May.

Abstract

Objective: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes.

Research design and methods: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay.

Results: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort.

Conclusions: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.

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Figures

Figure 1
Figure 1
Age at diagnosis of diabetes in individuals with DS diagnosed with diabetes (A) compared with individuals with type 1 diabetes from the BOX study (B).
Figure 2
Figure 2
A: The frequency (%) of type 1 diabetes–associated haplotypes in DSD children relative to age-matched children with type 1 diabetes (T1D), DS alone, and healthy control subjects (HC). B: The HLA characteristics of diabetes in children with DS by age at onset compared with type 1 diabetes.
See this image and copyright information in PMC

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