Development Of Islet Autoimmunity Research Articles

High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes—The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study

BackgroundThe Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow's milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies. ObjectiveOur primary aim was to study whether humoral immune responses to cow’s milk and cow’s milk consumption are associated with type 1 diabetes in TRIGR children. MethodsTRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002-2007 in 15 countries. Children were randomized into groups receiving extensively hydrolyzed casein or a regular cow’s milk formula and followed until age 10. Type 1 diabetes related autoantibodies and antibodies to cow’s milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with the risk to develop type 1 diabetes were analysed by Cox survival model. ResultsCow’s milk antibody levels both in cord blood [HR for islet autoimmunity 1.30 (95% CI 1.05-1.61); type 1 diabetes 1.32 (1.02-1.71)] and longitudinally from birth to 3 years [islet autoimmunity 1.39 (1.07-1.81); type 1 diabetes 1.43 (1.04-1.96)] were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with a reduced islet autoimmunity risk in the regular infant formula group [0.92 (0.85-0.99)]. Furthermore, frequent liquid milk consumption after infancy was associated with an increased risk of islet autoimmunity or type 1 diabetes. ConclusionsElevated cow's milk antibody levels and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody levels to cow’s milk may provide a biomarker of immune system prone to develop islet autoimmunity. Trial registry numberNCT00179777

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.

Detecting potential outliers in longitudinal data with time-dependent covariates.

Outliers can influence regression model parameters and change the direction of the estimated effect, over-estimating or under-estimating the strength of the association between a response variable and an exposure of interest. Identifying visit-level outliers from longitudinal data with continuous time-dependent covariates is important when the distribution of such variable is highly skewed. The primary objective was to identify potential outliers at follow-up visits using interquartile range (IQR) statistic and assess their influence on estimated Cox regression parameters. Study was motivated by a large TEDDY dietary longitudinal and time-to-event data with a continuous time-varying vitamin B12 intake as the exposure of interest and development of Islet Autoimmunity (IA) as the response variable. An IQR algorithm was applied to the TEDDY dataset to detect potential outliers at each visit. To assess the impact of detected outliers, data were analyzed using the extended time-dependent Cox model with robust sandwich estimator. Partial residual diagnostic plots were examined for highly influential outliers. Extreme vitamin B12 observations that were cases of IA had a stronger influence on the Cox regression model than non-cases. Identified outliers changed the direction of hazard ratios, standard errors, or the strength of association with the risk of developing IA. At the exploratory data analysis stage, the IQR algorithm can be used as a data quality control tool to identify potential outliers at the visit level, which can be further investigated.

Decrease in multiple complement proteins associated with development of islet autoimmunity and type 1 diabetes

Type 1 diabetes (T1D) is a chronic condition caused by autoimmune destruction of the insulin-producing pancreatic β cells. While it is known that gene-environment interactions play a key role in triggering the autoimmune process leading to T1D, the pathogenic mechanism leading to the appearance of islet autoantibodies-biomarkers of autoimmunity-is poorly understood. Here we show that disruption of the complement system precedes the detection of islet autoantibodies and persists through disease onset. Our results suggest that children who exhibit islet autoimmunity and progress to clinical T1D have lower complement protein levels relative to those who do not progress within a similar time frame. Thus, the complement pathway, an understudied mechanistic and therapeutic target in T1D, merits increased attention for use as protein biomarkers of prediction and potentially prevention of T1D.

SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood

The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.

Early Intervention by Family Physicians to Delay Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that target and destroy insulin-producing beta cells. Individuals with genetic risk of T1D will progress at variable rates through 3 stages of immune activation and development of islet autoimmunity. Measuring pancreatic islet cell autoantibodies predicts risk for progression that can take weeks to years before the onset of T1D. Screening options available to family physicians can identify persons at risk or in the early stages of T1D, such as first- and second-degree relatives or those with a family history of autoimmune disorders, to ultimately offer proven interventions that may delay or prevent the condition. Screening can reduce emergency room visits, hospitalizations, and intensive care unit admissions for diabetic ketoacidosis, which can be fatal, and can educate and prepare individuals and families for a smoother transition to insulin therapy when necessary. Recent advances in technology and understanding of the immune pathogenesis of T1D has resulted in emerging disease-modifying therapies that are changing how family physicians approach delaying and potentially preventing or reversing the disease.

Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study.

This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5-15 years. As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA-positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA-positive children, of whom 148 developed type 1 diabetes. No significant association was found in risk group 1 or risk group 2. A significant association was seen in risk group 3 (hazard ratio 0.920 [95% CI 0.856, 0.988] per 10-min increase; P = 0.021), particularly when glutamate decarboxylase autoantibody was the first autoantibody (hazard ratio 0.883 [95% CI 0.783, 0.996] per 10-min increase; P = 0.043). More daily minutes spent in moderate to vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in children aged 5-15 years who had developed multiple IAs.

What is the role of puberty in the development of islet autoimmunity and progression to type 1 diabetes?

In many populations, the peak period of incidence of type 1 diabetes (T1D) has been observed to be around 10–14 years of age, coinciding with puberty, but direct evidence of the role of puberty in the development of T1D is limited. We therefore aimed to investigate whether puberty and the timing of its onset are associated with the development of islet autoimmunity (IA) and subsequent progression to T1D. A Finnish population-based cohort of children with HLA-DQB1-conferred susceptibility to T1D was followed from 7 years of age until 15 years of age or until a diagnosis of T1D (n = 6920). T1D-associated autoantibodies and growth were measured at 3- to 12-month intervals, and pubertal onset timing was assessed based on growth. The analyses used a three-state survival model. IA was defined as being either positive for islet cell antibodies plus at least one biochemical autoantibody (ICA + 1) or as being repeatedly positive for at least one biochemical autoantibody (BC1). Depending on the IA definition, either 303 (4.4%, ICA + 1) or 435 (6.3%, BC1) children tested positive for IA by the age of 7 years, and 211 (3.2%, ICA + 1)) or 198 (5.3%, BC1) developed IA during follow-up. A total of 172 (2.5%) individuals developed T1D during follow-up, of whom 169 were positive for IA prior to the clinical diagnosis. Puberty was associated with an increase in the risk of progression to T1D, but only from ICA + 1-defined IA (hazard ratio 1.57; 95% confidence interval 1.14, 2.16), and the timing of pubertal onset did not affect the association. No association between puberty and the risk of IA was detected. In conclusion, puberty may affect the risk of progression but is not a risk factor for IA.

Dietary fatty acid intake in childhood and the risk of islet autoimmunity and type 1 diabetes: the DIPP birth cohort study

PurposeThe aim was to study the associations between dietary intake of fatty acids in childhood and the risk of islet autoimmunity and type 1 diabetes (T1D).MethodsThe prospective Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study included children with genetic susceptibility to T1D born between 1996 and 2004. Participants were followed up every 3 to 12 months up to 6 years for diet, islet autoantibodies, and T1D. Dietary intake of several fatty acids at the age of 3 months to 6 years was assessed 1–8 times per participant with a 3-day food record. Joint models adjusted for energy intake, sex, HLA genotype and familial diabetes were used to investigate the associations of longitudinal intake of fatty acids and the development of islet autoimmunity and T1D.ResultsDuring the 6-year follow-up, 247 (4.4%) children of 5626 developed islet autoimmunity and 94 (1.7%) children of 5674 developed T1D. Higher intake of monounsaturated fatty acids (HR 0.63; 95% CI 0.47, 0.82), arachidonic acid (0.69; 0.50, 0.94), total n-3 fatty acids (0.64; 0.48, 0.84), and long-chain n-3 fatty acids (0.14; 0.04, 0.43), was associated with a decreased risk of islet autoimmunity with and without energy adjustment. Higher intake of total fat (0.73; 0.53, 0.98), and saturated fatty acids (0.55; 0.33, 0.90) was associated with a decreased risk of T1D only when energy adjusted.ConclusionIntake of several fatty acids was associated with a decreased risk of islet autoimmunity or T1D among high-risk children. Our findings support the idea that dietary factors, including n-3 fatty acids, may play a role in the disease process of T1D.

Effects of Artificial Light at Night on Body Mass Index and Islet Autoimmunity Development in Children in Bavaria, Germany

Background and Aim: Worldwide, incidence of childhood obesity and early-onset type 1 diabetes (T1D) has risen over the past decades. Epidemiological studies have shown that in addition to genetic predisposition, environmental factors such as air pollution and temperature are associated with body mass index (BMI), T1D and its presymptomatic stage of autoimmunity to pancreatic islet cells. This study aimed to investigate the effect of exposure to light at night (LAN) on standardized BMI and islet autoimmunity (having 2 or more islet autoantibodies) in children in Bavaria, Germany. Methods: Exposure to LAN at baseline was assigned to the residential addresses of 52,636 children (&amp;#x3c;6 years of age) participating in the Fr1da study from 2015 to 2019. Information on demographic characteristics was extracted from self-administered questionnaires. We investigated the association of LAN with standardized BMI using linear regression and with islet autoimmunity using generalized additive models, segmented regression and quartile analysis. All models were adjusted for sex, age, family history of diabetes and area-level socioeconomic status (SES). Results: The mean standardized BMI was 0.12 &amp;#xb1; 1.04 and 225 children showed islet autoimmunity. A 10 nW/cm2/sr increase in LAN was significantly associated with a 2.14% increase in standardized BMI (95% confidence interval (CI): 0.86-3.45). Also, LAN exposure was linearly associated with a significantly higher odds of islet autoimmunity in children with exposure levels up to 11 nW/cm2/sr (Odds ratio (OR): 1.98; 95% CI: 1.14-3.45). Similar, quartile analyses showed a greater risk of islet autoimmunity especially for the third quartile (Q3: 5.2-11.6 nW/cm2/sr) of LAN compared to the lowest quartile (Q1: 0.0-2.0 nW/cm2/sr; OR: 1.71; 95% CI: 1.19-2.47). Conclusion: Exposure to LAN might be a further environmental risk factor contributing to higher BMI and islet autoimmunity in children. Keywords: Light at night, light pollution, body mass index, islet autoimmunity

Association of long-term environmental exposures in pregnancy and early life with islet autoimmunity development in children in Bavaria, Germany

ObjectiveIncidence of early-onset type 1 diabetes (T1D) has been increasing worldwide. Only few studies examined the relationship between geographical environmental variation and T1D incidence or its presymptomatic stage of islet autoimmunity. Our study aimed to investigate the effect of long-term environmental exposures during pregnancy and early life on childhood islet autoimmunity. Research Design and MethodsWe used data from the Fr1da cohort study which screened children aged 1.75–5.99 years for multiple islet autoantibodies in Bavaria, Germany between 2015 and 2019. We included 85,251 children with valid residential information. Daily averages for particulate matter with a diameter <2.5 μm, nitrogen dioxide, ozone, air temperature, and greenness were averaged for each zip-code or directly assigned to the addresses. The exposure windows included pregnancy, the first year and the first two years of life. Generalized additive models adjusting for individual and socioeconomic variables were used to investigate associations between environmental exposures and islet autoimmunity development. ResultsIslet autoimmunity was diagnosed in 272 children. Colder air temperature during pregnancy was associated with developing islet autoimmunity at the address (per 2.2 °C decrease, Odds ratio (OR): 1.49; 95% Confidence interval (CI): 1.21–1.83) and zip-code level (per 2.4 °C decrease, OR: 1.31; 95% CI: 1.08–1.59). Using the addresses, significant associations were also observed during the first years of life. ConclusionIn this study, children's residential exposure to lower levels of air temperature during pregnancy and early life increased the risk of islet autoimmunity before the age of six.

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.

Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study

The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3–4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case–control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52–5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.

Childhood Height Growth Rate Association With the Risk of Islet Autoimmunity and Development of Type 1 Diabetes.

ContextRapid growth has been suggested to promote islet autoimmunity and progression to type 1 diabetes (T1D). Childhood growth has not been analyzed separately from the infant growth period in most previous studies, but it may have distinct features due to differences between the stages of development.ObjectiveWe aimed to analyze the association of childhood growth with development of islet autoimmunity and progression to T1D diagnosis in children 1 to 8 years of age.MethodsLongitudinal data of childhood growth and development of islet autoimmunity and T1D were analyzed in a prospective cohort study including 10 145 children from Finland, Germany, Sweden, and the United States, 1-8 years of age with at least 3 height and weight measurements and at least 1 measurement of islet autoantibodies. The primary outcome was the appearance of islet autoimmunity and progression from islet autoimmunity to T1D.ResultsRapid increase in height (cm/year) was associated with increased risk of seroconversion to glutamic acid decarboxylase autoantibody, insulin autoantibody, or insulinoma-like antigen-2 autoantibody (hazard ratio [HR] = 1.26 [95% CI = 1.05, 1.51] for 1-3 years of age and HR = 1.48 [95% CI = 1.28, 1.73] for >3 years of age). Furthermore, height rate was positively associated with development of T1D (HR = 1.80 [95% CI = 1.15, 2.81]) in the analyses from seroconversion with insulin autoantibody to diabetes.ConclusionRapid height growth rate in childhood is associated with increased risk of islet autoimmunity and progression to T1D. Further work is needed to investigate the biological mechanism that may explain this association.

Association of Environmental Exposures in Pregnancy and Early Life with Islet Autoimmunity Development in Children in Bavaria, Germany

Association of Environmental Exposures in Pregnancy and Early Life with Islet Autoimmunity Development in Children in Bavaria, Germany

Extended family history of type 1 diabetes in HLA-predisposed children with and without islet autoantibodies

Objective The aim of this study was to explore the extended family history of type 1 diabetes in children at genetic risk and define the impact of a positive family history on the development of islet autoimmunity and type 1 diabetes. Methods The subjects were participants in The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and carried increased HLA-conferred risk for type 1 diabetes. The case children (n=343) were positive for at least one islet autoantibody, and the control children (n=343) matched by age, gender and class II HLA genotype were negative for islet autoantibodies at the time of data collection. Extended family history of type 1 diabetes was obtained by using a structured questionnaire. Results Among children who were autoantibody positive and progressed to type 1 diabetes 62.2% (28/45) had at least one relative with type 1 diabetes. Interestingly, 57.8% of these children (26/45) had such a relative outside the nuclear family compared to 30.7% of children with no autoantibodies (P=0.001), 35.2% of those with only classical islet cell antibodies (P=0.006), and 35.2% of non-progressors with biochemical autoantibodies (P=0.011). A positive history of type 1 diabetes in the paternal extended family was more common in children with multiple biochemical autoantibodies compared to those with only one biochemical autoantibody (P=0.010). No association between the specificity of the first appearing autoantibody and family history of the disease was found. Conclusions Type 1 diabetes in relatives outside the nuclear family is a significant risk factor for islet autoimmunity and progression to clinical disease in HLA susceptible children. This article is protected by copyright. All rights reserved.

The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children.

Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3–5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.

1125-P: Do Non-HLA Genes Contribute to Age of Type 1 Diabetes Onset in Monozygotic Twins?

Development of islet autoimmunity (IA) and type 1 diabetes (T1D) are associated with high-risk HLA class II loci as well as non-HLA genes. Monozygotic (MZ) twins have a high rate of concordance to T1D progression after the first twin develops T1D, especially for those diagnosed at a young age. We analyzed 52 T1D-associated non-HLA SNPs from ImmunoChip data in 159 MZ twins from the Twin Family Study: 79 twin probands with T1D and their 80 unaffected cotwins/triplets (including one set of triplets). Subjects are enrolled into the Twin Study when the proband is diagnosed with T1D and cotwins are followed longitudinally for the development of IA and/or T1D. In the cotwins, we analyzed the association between each of the non-HLA SNPs and IA after adjusting for HLA DR3/4*0302. In the twin probands with T1D, we used a linear regression model to evaluate the association of non-HLA SNPs with diabetes age at onset after adjusting for HLA DR3/4*0302. Median (IQR) age of diagnosis of the twin probands was 9.9 (5.4-13.9) years and age of last visit for the cotwins was 17.5 (11.2-26.7) years. Of the 80 cotwins, 41 (51.3%) developed IA and 15 (18.8%) were diagnosed with T1D. After adjusting for HLA DR3/4*0302, SNPs in CTLA4 (rs3087243), IL2 (rs4505848), IKZF1 (rs62447205), and INS (rs7111341) were found to be associated with the development of IA in cotwin subjects (all p&amp;lt;0.04). After adjusting for HLA DR3/4*0302, SNPs in CTSH (rs3825932) and TYK2 (rs34536443) were found to be associated with younger age of diabetes onset in the twin probands (p&amp;lt;0.05). In this cohort of MZ twins, non-HLA SNPs in CTSH and TYK2, which function both in the immune system and in beta cells, were associated with younger age of onset in the twin probands. Further studies are needed to evaluate the specific role of these genes for immunity and T1D onset. Disclosure T. M. Triolo: None. F. Dong: None. H. C. Broncucia: None. S. Onengut-gumuscu: None. A. Steck: None. S. S. Rich: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094712)

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes.

OBJECTIVEEnvironmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.RESEARCH DESIGN AND METHODSAssociation between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes (n = 271) or multiple diabetes-associated islet autoantibodies (n = 384) and children without diabetes who are negative for diabetes autoantibodies.RESULTSAgricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16–0.87, P = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, P = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, P = 0.001) compared with an urban environment known to have lower environmental microbial diversity.CONCLUSIONSThe study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.

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

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. Participants in a randomised infant feeding trial (N = 2149) were measured at 12month 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 10-14years. 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. 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 10years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10years 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. In children at genetic risk of type 1 diabetes, being overweight at 2-10years 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. ClinicalTrials.gov NCT00179777.