Study Assesses Optimal Ages for T1D Screening

The risk of developing islet autoimmunity—which precedes clinical type 1 diabetes (T1D)—declines exponentially with age, according to research published in Diabetes Care. Findings also indicate the influence of major genetic factors on this risk is limited to the first few years of life.

“Age is a modulator of autoimmune diseases,” the authors wrote, while “most autoimmune diseases show periods of high and low incidence, and these differences are likely to have an etiological basis.”

As the rate at which the risk of islet autoantibody seroconversion attenuates may provide insight to the timing of events that cause or protect against autoimmunity, investigators assessed the age-related decline in risk among participants in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

The prospective study included over 8000 children in the United States and Europe, selected based on their genetic predisposition to T1D. Throughout the investigation, the researchers monitored the development of islet autoantibodies from birth and conducted quarterly measurements of autoantibodies to multiple pancreatic antigens. This provided an opportunity to model seroconversion to distinct autoantibody phenotypes throughout participants’ childhoods.

A total of 8556 children (49.4% girls) were included in the current analysis and around 11% (n = 955) had a first-degree family history of T1D. Overall, “809 of 8556 children (9.46%; 95% CI, 8.85%-10.1%) enrolled in the TEDDY study developed islet autoantibodies at a median age of 3.2 years (interquartile range [IQR], 1.5-6.5), including 471 who developed multiple islet autoantibodies within a median time of 0.3 years (IQR, 0.0-1.0) after becoming islet-autoantibody positive,” authors wrote.

Additional analyses revealed:

• The first autoantibody-positive samples in children who developed multiple islet autoantibodies most frequently contained islet autoantibodies against insulin (IAA) only (n = 166), glutamic acid decarboxylase autoantibodies (GADA) only (n = 161), or multiple islet autoantibodies (n = 133)
• Most of the 338 children with one islet autoantibody had IAA (n = 136) or GADA (n = 190)
• The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI, 3.8%-4.7%) at 7.5 months of age and declined to 1.1% (95% CI, 0.8%-1.3%) at a landmark age of 6.25 years (P < .0001)
• Risk decline was slight or absent in single insulin and GADA phenotypes
• The influence of sex, human leukocyte antigen (HLA), and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years
• Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for T1D was achieved by autoantibody screening at 2 years and again at 5–7 years

Data suggest that a portion of the genetic contribution to the development of multiple islet autoantibodies and T1D decreases before puberty.

“The relative reduction in the frequency of HLA DR-DQ risk genotypes in patients with older-onset T1D compared with childhood onset, the increased contribution of several susceptibility genes to younger-onset T1D, and the relatively small impact of T1D susceptibility genes with progression to diabetes in children positive for multiple islet autoantibodies are consistent with this finding,” the researchers wrote.

Although no single time point captured the majority of T1D cases occurring by the age of 12, the highest sensitivity was achieved when screening between ages 3 and 5 years, while screening genetically at-risk children at 2 time points increased sensitivity.

Selection of children based on their HLA genotype to participate in the study marks a limitation, as findings may not be generalizable to those at lower genetic risk. The small number of children monitored until teenage years also marks a limitation.

However, “we have shown that the first years of life represent a period of heightened risk of developing T1D-relevant autoimmunity and that the risk declined exponentially with age in childhood,” the authors said.

“The findings have practical implications for implementing population-based screening and have led to models for explaining the development of islet autoimmunity. We suggest that our understanding of the etiological causes of T1D will be improved by the findings of future studies aimed at confirming or refuting these models,” they concluded.

Reference

Bonifacio E, Weiss A, Winkler C, et al; TEDDY Study Group. An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood. Diabetes Care. Published online February 24, 2021. doi:10.2337/dc20-2122