Dataset Information

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

ABSTRACT:

Aims/hypothesis

We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes.

Methods

Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10-14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05.

Results

In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling.

Conclusions/interpretation

In children at genetic risk of type 1 diabetes, being overweight at 2-10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes.

Trial registration

ClinicalTrials.gov NCT00179777.

SUBMITTER: Nucci AM

PROVIDER: S-EPMC7940594 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

Nucci Anita M AM Virtanen Suvi M SM Cuthbertson David D Ludvigsson Johnny J Einberg Ulle U Huot Celine C Castano Luis L Aschemeier Bärbel B Becker Dorothy J DJ Knip Mikael M Krischer Jeffrey P JP

Diabetologia 20210121 4

<h4>Aims/hypothesis</h4>We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes.<h4>Methods</h4>Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and ...[more]

PMID: 33474583

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Project description:ObjectiveWe tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.Research design and methodsWe studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.ResultsHigher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).ConclusionsThe T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.

Project description:BackgroundProspective longitudinal evidence considering the entire childhood food consumption in relation to the development of islet autoimmunity (IA or) type 1 diabetes is lacking.ObjectivesWe studied the associations of consumption of various foods and their combinations with IA and type 1 diabetes risk.MethodsChildren with genetic susceptibility to type 1 diabetes born in 1996-2004 were followed from birth up to ≤6 y of age in the prospective birth cohort type 1 diabetes prediction and prevention study (n = 5674). Exposure variables included 34 food groups covering the entire diet based on repeated 3-d food records at ages 3 mo to 6 y. Endpoints were islet cell antibodies plus biochemical IA (n = 247), multiple biochemical IA (n = 206), and type 1 diabetes (n = 94). We analyzed associations between longitudinally observed foods and risk of IA/type 1 diabetes using a Bayesian approach to joint models in 1-food and multi-food models adjusted for energy intake, sex, human leukocyte antigen genotype, and familial diabetes.ResultsThe final multi-food model for islet cell antibodies plus biochemical IA included oats [hazard ratio (HR): 1.09; 95% credible interval (CI): 1.04, 1.14], banana (HR: 1.07; 95% CI: 1.03, 1.11), and cruciferous vegetables (HR: 0.83; 95% CI: 0.73, 0.94). The final model for multiple biochemical IA included, in addition to the above-mentioned foods, fermented dairy (HR: 1.42; 95% CI: 1.12, 1.78) and wheat (HR: 1.10; 95% CI: 1.03, 1.18). The final multi-food model for type 1 diabetes included rye (HR: 1.27; 95% CI: 1.07, 1.50), oats (HR: 1.15; 95% CI: 1.03, 1.26), fruits (HR: 1.05; 95% CI: 1.01, 1.09), and berries (HR: 0.67; 95% CI: 0.50, 0.93).ConclusionsHigher consumption of oats, gluten-containing cereals, and fruits was associated with increased that of cruciferous vegetables with decreased risk of several type 1 diabetes-related endpoints when considering all the foods in combination. Further etiological and mechanistic studies are warranted.

Project description:ObjectiveThere are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.Research design and methodsSubjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.ResultsAt screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.ConclusionsRisk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

Dataset Information

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Trial registration

Publications

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

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