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Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.

ABSTRACT: Aims/hypothesis: The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.

Methods: In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.

Results: Multiple autoantibodies (?2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p?
Conclusions/interpretation: The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.

Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract.

SUBMITTER: Pacaud D

PROVIDER: S-EPMC7716821 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.

Pacaud Danièle D Nucci Anita M AM Cuthbertson David D Becker Dorothy J DJ Virtanen Suvi M SM Ludvigsson Johnny J Ilonen Jorma J Knip Mikael M

Diabetologia 20201007 1

<h4>Aims/hypothesis</h4>The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.<h4>Methods</h4>In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were c ...[more]

PMID: 33026463

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Project description:Aims/hypothesisWe 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.MethodsParticipants 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.ResultsIn 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/interpretationIn 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 registrationClinicalTrials.gov NCT00179777.

Project description:Aims/hypothesisIdentifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.MethodsWe studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.ResultsOf the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.Conclusions/interpretationWe have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.

Project description:Aims/hypothesisThe aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity.MethodsBetween February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk.ResultsThe COVID-19 pandemic was associated with increased time-varying BMI (β = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months (β = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI (β = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months (β = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months (β = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively).Conclusions/interpretationEarly-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes.

Project description:BackgroundThe incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes.Methods/designENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests.DiscussionDefining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity.Trial registrationAustralia New Zealand Clinical Trials Registry ACTRN12613000794707.

Project description:Whether categories of family history of diabetes can act as independent risk factors for gestational diabetes mellitus (GDM-1, -2) has not yet been established, and neither has it been established how categories of body mass index (BMI) affect these relationships. A group of 912 women without chronic diseases, recruited in the first trimester, was investigated: 125 (13.7%) women developed GDM-1 (treated with diet); 21 (2.3%) women developed GDM-2 (treated with insulin); and a control group consisted of 766 non-diabetic women. A multiple logistic regression was used to evaluate adjusted odds ratios (AOR (95% confidence intervals)) of GDM-1 and GDM-2 for declared diabetes in the parents or grandparents (separately). These relationships were investigated in the whole cohort and subgroups of pre-pregnancy BMI. (1) Some categories of the family history were independent risk factors of GDM-1 or GDM-2. Compared to 'absence of diabetes in the family', women with diabetes in the father had a 3.68-fold increase in GDM-1 risk (AOR-b = 3.68 (2.23-6.07)), and women with diabetes in the mother had a 2.13-fold increase in GDM-1 risk (AOR-b = 2.13 (1.1-4.14)) and a 4.73-fold increase in GDM-2 risk (AOR-b = 4.73 (1.26-17.77)). Women with diabetes in the grandmother had a 2.34-fold increase in GDM-1 risk (AOR-b = 2.34 (1.29-4.24)). (2) The cumulative assessment of diabetes in the parents and/or grandparents was not related to the intensification of the risk of GDM, except for the increased risk of GDM-1 for diabetes in both mother and grandmothers simultaneously (AOR-b = 8.80 (1.16-66.57)), however, this group was very small. (3) The analyses in the subgroups of BMI categories showed that diabetes in the father was also an independent risk factor of GDM in the subgroup of pregnant women with normal BMI. In the subgroups of overweight and/or obesity, the risk of GDM for paternal and maternal diabetes was approximately twice as high as compared to the results of pregnant women with normal BMIs. Additionally, apart from the maternal influence of diabetes, the results suggest a significant influence of diabetes in the father on the risk of GDM, even (interestingly) in lean pregnant women.

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Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.

Publications

Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.

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