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Diabetes Care. 2017 Aug;40(8):1065-1072. doi: 10.2337/dc16-2228.

Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and HLA-DQ Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes.

Author information

1
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
2
Department of Clinical Chemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium.
3
Department of Diabetology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium.
4
Department of Endocrinology, Universitair Ziekenhuis Leuven, Leuven, Belgium.
5
Department of Endocrinology, Diabetology and Metabolism, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium.
6
Department of Diabetology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
7
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium ilse.weets@uzbrussel.be.

Abstract

OBJECTIVE:

We investigated whether islet autoantibody profile, HLA-DQ genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb+) in first-degree relatives of patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS:

Persistently islet autoAb+ siblings and offspring (n = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay.

RESULTS:

The 20-year progression rate of multiple-autoAb+ relatives (n = 194) was higher than that for single-autoAb+ participants (n = 268) (88% vs. 54%; P < 0.001). Relatives positive for IAA and GADA (n = 54) progressed more slowly than double-autoAb+ individuals carrying IA-2A and/or ZnT8A (n = 38; P = 0.001). In multiple-autoAb+ relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes (P < 0.001); in single-autoAb+ relatives, it identified younger age (P < 0.001), HLA-DQ2/DQ8 genotype (P < 0.001), and IAA (P = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (P = 0.042), HLA-DQ2/DQ8 genotype (P = 0.009), and the development of additional autoAbs (P = 0.012) were associated with more rapid progression to diabetes.

CONCLUSIONS:

In single-autoAb+ relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and HLA-DQ2/DQ8 genotype. The majority of multiple-autoAb+ individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, HLA-DQ genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.

PMID:
28701370
DOI:
10.2337/dc16-2228
[Indexed for MEDLINE]

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