Overview
The incidence of type 1 diabetes (T1D) in children is increasing worldwide, with the number of people living with T1D globally predicted to rise significantly in the coming decades. While genetics play a role in T1D risk, the growing incidence cannot be solely explained by genetic factors. Environmental influences and gene-environment interactions are believed to be key drivers of this trend.
The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an Australian, prospective, observational cohort study investigating how modifiable prenatal and early-life exposures impact the development of islet autoimmunity and ultimately, T1D. Launched in 2013, ENDIA is following children who have a first-degree relative (FDR) with T1D, from pregnancy through childhood.
Significance of Early-Life Factors
Seroconversion to islet autoimmunity, the precursor to T1D, typically occurs in early life, indicating that initiators and protectors of the autoimmune process are encountered during pregnancy and infancy. Large prospective birth cohorts have highlighted the importance of investigating exposures from pregnancy and the first years of life to understand the developmental origins of T1D.
Several prenatal and postnatal factors have been linked to altered T1D risk, including maternal obesity, diet, infections, mode of delivery, weight gain, and early feeding practices. The rapid changes in the infant gut microbiome, influenced by these early-life exposures, may also play a key role in shaping immune function and susceptibility to autoimmunity.
Aims of the ENDIA Study
The overarching goal of ENDIA is to identify the gene-environment interactions that drive the development of islet autoimmunity and progression to clinical T1D in genetically at-risk children. By prospectively following participants from pregnancy through childhood, the study aims to:
- Characterize the maternal and infant microbiome, and evaluate how it is shaped by prenatal and postnatal exposures.
- Investigate the impact of maternal factors (e.g., obesity, diet, infections) and infant growth, feeding, and immune function on the risk of islet autoimmunity.
- Integrate longitudinal multi-omic data (e.g., metabolome, lipidome, epigenome) to uncover novel biomarkers and pathways underlying the initiation and progression of autoimmunity.
- Ultimately, inform primary prevention strategies that could be implemented in early life to reduce the burden of T1D.
Comprehensive Cohort Profile
ENDIA is the first study worldwide to investigate the developmental origins of T1D with such a comprehensive, longitudinal approach, starting from pregnancy. The study profile published in 2024 provides valuable insights into the cohort’s characteristics and methodology.
Participant Recruitment and Eligibility
The ENDIA cohort comprises 1,473 infants born to 1,214 gestational mothers across 1,453 pregnancies, with 80% enrolled during pregnancy. Eligibility was based solely on having an FDR with T1D, regardless of the child’s human leukocyte antigen (HLA) genotype.
This inclusive approach is unique compared to other major birth cohorts, which often exclude children with lower-risk HLA genotypes. The rationale is that the rising incidence of T1D is being driven by individuals with moderate-risk HLA types, rather than just those with the highest-risk genotypes.
Participant Characteristics
The ENDIA cohort reflects the diversity of the Australian population, with a few key differences:
- A higher proportion of parents were Australian-born, lived in major cities, and had higher socioeconomic status and education levels compared to the general population.
- Mothers with T1D had higher rates of pregnancy complications, perinatal interventions, and delivered larger babies at a shorter gestation.
- The distribution of familial T1D probands was 62% maternal, 28% paternal, and 11% sibling.
- The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members.
Comprehensive Data Collection
ENDIA participants are followed longitudinally, with data and biospecimen collection occurring:
- During pregnancy (every trimester)
- At birth (within the first week)
- Every 3 months until 2 years of age
- Every 6 months thereafter until 10 years of age
This extensive data collection includes demographic information, lifestyle factors, clinical measurements, dietary intake, and a wide range of biological samples (blood, urine, stool, swabs) for multi-omic analyses.
Nested Case-Control Study
To investigate the relationship between longitudinal omics exposures and the development of persistent islet autoimmunity, a nested case-control (NCC) study is currently underway within the ENDIA cohort. This NCC study aims to analyze approximately 16,000 samples collected from 190 children, including 54 who have developed persistent islet autoimmunity.
Study Design and Participant Selection
The NCC study uses a matched design, where cases are children who have developed persistent islet autoimmunity, and controls are children who remain islet autoantibody-negative. Controls are matched to cases by sex, age, and the absence of all four islet autoantibodies within a defined window of the case’s seroconversion.
Longitudinal Omics Analyses
The NCC study will leverage the extensive ENDIA biospecimen collection to generate longitudinal data on various omics layers, including:
- Microbiome (gut, oral, nasal, skin)
- Metabolome
- Lipidome
- Epigenome
These multi-omic datasets will enable a comprehensive investigation of the dynamic molecular changes from pregnancy through early childhood that may contribute to the initiation and progression of islet autoimmunity.
Analytical Approach
The NCC study will employ both univariate and multivariate statistical methods to identify associations between the longitudinal omics exposures and the development of persistent islet autoimmunity. Given the exploratory, discovery-focused nature of the study, the analytical approaches will need to account for the complexity of the longitudinal, multi-omic data.
Significance and Collaborations
The ENDIA Study represents a globally significant resource for understanding the complex interplay of genetics, environment, and their impact on biological systems in the development of T1D. By prospectively investigating exposures from pregnancy onwards, the study aims to inform new primary prevention strategies that could be implemented in early life.
ENDIA is involved in numerous national and international collaborations, and welcomes opportunities for further collaboration with researchers interested in investigating the developmental origins of type 1 diabetes. Researchers can contact the ENDIA team at [email protected] to inquire about potential collaborations and data access.
To learn more about the ENDIA Study, please visit the ENDIA website. The Stanley Park High School community is encouraged to stay informed about this important research, as the findings may have implications for families and children at risk of developing type 1 diabetes.
