Genetic and environmental drivers shape early type 1 diabetes risk in children

By examining early autoimmunity triggers, TEDDY study researchers reveal how genetics, infections, and diet uniquely shape type 1 diabetes risk, offering new directions for prevention in at-risk children.

Looking back at the TEDDY study: lessons and future directions. Image Credit: Image Point Fr / Shutterstock

In a recent review published in the journal Nature Reviews Endocrinology, a group of authors identified the factors contributing to the onset of islet autoimmunity (autoantibodies appearing against insulin and GAD65 early in life, signaling the body’s immune response) and the progression to type 1 diabetes mellitus (T1DM) in children.

Background

T1DM is a significant chronic illness that primarily affects children and young adults but can arise at any age, with about 50% of cases presenting in adults. Characterized by chronic hyperglycemia, T1DM results from the autoimmune destruction of insulin-producing β cells, often initiated by the early appearance of insulin autoantibodies (IAA) or glutamic acid decarboxylase autoantibodies (GADA).

While T1DM is linked to certain Human Leukocyte Antigen (HLA) class II genotypes, genetic factors alone cannot fully account for its onset, as environmental influences such as diet, pathogens, and psychosocial factors play a crucial role. In particular, the timing and nature of certain viral exposures may influence the likelihood of IAA or GADA appearing first, which carries distinct implications for disease progression.

Further research is essential to identify the environmental triggers of islet autoimmunity and T1DM.

Screening and enrollment

Recruitment posed various challenges, with only about 40% of eligible infants participating. Many families cited concerns over blood draws or the demanding nature of the study protocol as reasons for declining. Despite these challenges, the study achieved high retention rates, particularly in Finland and Sweden.

Behavioral and psychological factors such as parent perceptions of disease risk and study satisfaction were significant predictors of retention. Ethnic minority families in the United States of America (USA) showed higher drop-out rates, which were influenced by behavioral and psychological factors, such as parental anxiety regarding their child’s risk of T1DM.

Understanding islet autoimmunity

The progression of islet autoimmunity leading to T1DM involves different phenotypes characterized by the first-appearing autoantibodies. The TEDDY study observed that IAA-first and GADA-first profiles have distinct onset patterns and genetic backgrounds, with HLA-DR4-DQ8 often linked to IAA-first and HLA-DR3-DQ2 to GADA-first. Insulin Autoantibodies (IAA) and Glutamic Acid Decarboxylase Autoantibodies (GADA) are usually the first autoantibodies detected, with the highest seroconversion rates occurring between 6 months and 3 years of age.

The study revealed distinct patterns of autoantibody appearance, indicating a need for targeted surveillance in high-risk populations.

Genetic factors

Genetic risk accounts for approximately 50% of T1DM cases, with specific HLA-DR and HLA-DQ alleles contributing significantly to susceptibility. TEDDY’s comprehensive genomic analyses have identified over 100 loci associated with T1DM.

The study’s design allowed for the identification of genetic variants that modulate the impact of environmental triggers, suggesting different underlying mechanisms for IAA-first versus GADA-first profiles and enhancing the understanding of the disease’s multifaceted nature.

Environmental influences

The study explored various environmental factors, including infections, diet, and psychosocial stressors, that may influence the onset of islet autoimmunity. Among infections, enteroviruses—especially Coxsackie B species—were linked to increased risks of IAA-first, while early-life exposure to adenovirus C appeared protective against islet autoimmunity, possibly by stimulating antiviral defenses.

Additionally, early-life dietary patterns, such as the timing of gluten introduction and the intake of probiotics, were investigated for their potential role in modulating autoimmunity risk.

The competing risk of coeliac disease autoimmunity (CDA)

In the TEDDY study, children were screened annually for tissue transglutaminase antibodies (TGA), and those with persistently positive results were diagnosed with CDA. Data from the TEDDY study indicate that the highest incidence of CDA diagnoses occurs between the ages of 1 and 4 years, with rates three to four times higher than those for IAA-first and two to three times higher than for GADA-first. HLA-DR3-DQ2 homozygosity was identified as the strongest risk factor for CDA, presenting a five-fold increased risk.

Other contributing factors include the presence of IAA-first or GADA-first autoantibodies, family history of T1DM, and certain genetic variations. The early incidence of CDA may influence the development of GADA as the first autoantibodies to appear in those with specific HLA haplotypes. Competing enterovirus infections may also play a role, as one virus might inhibit the infection by another, affecting the onset of autoimmunity.

Further genetic studies identified 54 single nucleotide polymorphisms (SNPs) associated with CDA, underscoring the complex interplay of genetics and environmental exposures. Interestingly, perinatal factors such as delivery method and maternal diet during pregnancy were not significantly linked to CDA risk, though low and high vitamin D levels were associated with increased risk.

High gluten intake consistently correlated with CDA development, while no connection was found between antibiotic use and CDA risk.

Conclusions

To summarize, the first primary outcome of the TEDDY study aims to identify factors leading to the initiation of islet autoimmunity, evidenced by IAA-first, GADA-first, or both, revealing distinct patterns of associated factors.

Studies of the TEDDY cohort revealed that serious life events during pregnancy, infant growth, and early dietary exposures could differently impact IAA and GADA phenotypes. While the second primary outcome, concerning progression to clinical onset, also indicates early associated factors, the final analysis awaits the completion of sample collection by early 2025.

The TEDDY study’s large, well-retained cohort with high genetic and environmental risk has provided valuable insights for predictive models and targeted interventions. Genetic and environmental factors, including serious life events and dietary influences, differentially affect the phenotypes of autoimmunity.