The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study

Abstract

Aims/hypothesis: Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both.

Methods: Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter.

Results: Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children.

Conclusions/interpretation: Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.

Fig. 1

Incidence of antibodies among 0- to 6-year-old children in the TEDDY study by age of seroconversion (incidence and 95% piecewise confidence bands). Autoantibodies appeared in 549/8,503 children

Fig. 2

Incidence of IAA only (dark grey lines and squares), GADA only (black lines and circles) and IAA and GADA only (light grey lines and triangles) in all participants (a), GP (b) or FDR (c) of a proband with type 1 diabetes. In (a), of 8,503 children, IAA only appeared in 240, GADA only in 207 and IAA and GADA in 76. In (b), of 7,584 children, IAA only appeared in 184, GADA only in 166 and IAA and GADA in 58. In (c), of 919 children, IAA only appeared in 56, GADA only in 41 and IAA and GADA in 18

Fig. 3

Incidence of IAA only (dark grey lines and squares), GADA only (black lines and circles) and IAA and GADA only (light grey lines and triangles) by HLA genotype: DR3/4 (a), DR4/8 (b), DR4/4 (c) and DR3/3 (d). In (a), of 3,318 children, IAA only appeared in 120, GADA only in 101 and IAA and GADA in 49. In (b), of 1,470 children, IAA only appeared in 51, GADA only in 21 and IAA and GADA in 6. In (c), of 1,660 children, IAA only appeared in 42, GADA only in 31 and IAA and GADA in 10. In (d), of 1,781 children, IAA only appeared in 14 children, GADA only in 50 and IAA and GADA in 3