Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups.

Background: Anatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes. Methods: The Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated. Results: We observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups. Conclusion: We report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones.

First-emerging islet autoantibody and glucose metabolism: search for type 1 diabetes subtypes.

Objective: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3-12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n = 143), GAD antibody (GADA) multiple (n = 126) and islet antigen 2 antibody (IA-2A) multiple (n = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n = 87), GADA only (n = 114) and IA-2A only (n = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

Effects of Randomized Controlled Infancy-Onset Dietary Intervention on Leukocyte Telomere Length-The Special Turku Coronary Risk Factor Intervention Project (STRIP).

Reduced telomere length (TL) is a biological marker of aging. A high inter-individual variation in TL exists already in childhood, which is partly explained by genetics, but also by lifestyle factors. We examined the influence of a 20-year dietary/lifestyle intervention on TL attrition from childhood to early adulthood. The study comprised participants of the longitudinal randomized Special Turku Coronary Risk Factor Intervention Project (STRIP) conducted between 1990 and 2011. Healthy 7-month-old children were randomized to the intervention group (n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group (n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years (n = 232; intervention n = 108, control n = 124). Yearly TL attrition rate was calculated. The participants of the intervention group had slower yearly TL attrition rate compared to the controls (intervention: mean = -7.5 bp/year, SD = 24.4 vs. control: mean = -15.0 bp/year, SD = 30.3; age, sex and baseline TL adjusted ß = 0.007, SE = 0.004, p = 0.040). The result became stronger after additional adjustments for dietary fat quality and fiber intake, serum lipid and insulin concentrations, systolic blood pressure, physical activity and smoking (ß = 0.013, SE = 0.005, p = 0.009). A long-term intervention focused mainly on dietary fat quality may affect the yearly TL attrition rate in healthy children/adolescents.

Attainment of Targets of the 20-Year Infancy-Onset Dietary Intervention and Blood Pressure Across Childhood and Young Adulthood: The Special Turku Coronary Risk Factor Intervention Project (STRIP).

We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention was associated with blood pressure (BP) from infancy to young adulthood. In the prospective randomized STRIP (Special Turku Coronary Risk Factor Intervention Project; n=877 children), dietary counseling was provided biannually based on the Nordic Nutrition Recommendations primarily to improve the quality of dietary fat in children's diets and secondarily to promote intake of vegetables, fruits, and whole grains. Dietary data and BP were accrued annually from the age of 13 months to 20 years. The dietary targets for fat quality were defined as the ratio of saturated fatty acids to monounsaturated and polyunsaturated fatty acids <1:2 and intake of saturated fatty acids <10 E%, dietary fiber intake in the top age-specific quintile, and dietary sucrose intake as being in the lowest age-specific quintile. Attaining a higher number of the dietary targets was associated with lower systolic BP (mean [SE] systolic BP, 107.3 [0.3], 107.6 [0.3], 106.8 [0.3], and 106.7 [0.5] mm Hg in participants meeting 0, 1, 2, and 3 to 4 targets, respectively; P=0.03) and diastolic BP (mean [SE] diastolic BP, 60.4 [0.2], 60.5 [0.2], 59.9 [0.2], and 59.9 [0.3] mm Hg; P=0.02). When the lowest age-specific quintile of dietary cholesterol was added as an additional target, the association with systolic BP remained significant (P=0.047), but the association with diastolic BP attenuated (P=0.13). Achieving the key targets of an infancy-onset 20-year dietary intervention, reflecting dietary guidelines, was favorably albeit modestly associated with systolic and diastolic BP from infancy to young adulthood. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00223600.

Temperament profiles are associated with dietary behavior from childhood to adulthood.

BACKGROUND AND OBJECTIVES: Temperament may be associated with eating behaviors over the lifespan. This study examined the association of toddlerhood temperament with dietary behavior and dietary intervention outcomes across 18 years. METHODS: The study comprised 660 children (52% boys) from The Special Turku Intervention Project (STRIP), which is a longitudinal randomized controlled trial from the age of 7 months until the age of 20 years (1990-2010). Temperament was assessed using Carey temperament scales when the participants were 2 years of age. Latent profile analysis yielded three temperament groups, which were called negative/low regulation (19% of the children), neutral/average regulation (52%) and positive/high regulation (28%). Dietary behavior was examined from 2 to 20 years of age using food records, which were converted into a diet score (mean = 15.7, SD 4.6). Mixed random-intercept growth curve analysis was the main analytic method. RESULTS: Dietary behavior showed a significant quadratic U-shaped curve over time (B for quadratic association = 0.39, P<.001; B for linear association = 0.09, P = 0.58). Children in the negative/low regulation temperament group had a lower diet score (less healthy diet) across the 18 years compared to children in the neutral/average or in the positive/high regulation group. Temperament was not associated with the rate of change in diet over time. Temperament did not have any interactive effects with the intervention (F [2, 627], P = 0.72). CONCLUSION: Children with a temperament profile characterized by high negative mood, high irregularity and high intensity in emotion expression constitute a risk group for less healthy eating over the lifespan.

Effects of 20-year infancy-onset dietary counselling on cardiometabolic risk factors in the Special Turku Coronary Risk Factor Intervention Project (STRIP): 6-year post-intervention follow-up.

BACKGROUND: Primordial and primary prevention is the cornerstone for cardiometabolic health. In the randomised, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP; n=1116), a 20-year dietary counselling intervention was given to children biannually from infancy, and cardiometabolic health benefits had been observed among the participants in the intervention group. Here, we report on the key results of the first follow-up done 6 years after the end of the intervention, at age 26 years. METHODS: The randomised controlled STRIP study recruited children at age 5 months from well-baby clinics in Turku, Finland, and randomly assigned them to either an intervention or control group; group allocation was unmasked. The intervention introduced participants to a heart-healthy diet, characterised by low proportional intake of saturated fat and cholesterol, by dietary counselling and nutrition education sessions to parents and children from the age of 7 months to 20 years. Children in the control group received only the basic health education given at Finnish well-baby clinics and school health care. We assessed diet, lifestyle, and cardiometabolic risk factor data, including blood pressure, anthropometry, serum biochemistry (lipids, apolipoproteins, glucose, and insulin), and homoeostatic model assessment of insulin resistance (HOMA-IR) in the participants at age 26 years. FINDINGS: 1116 children were included in the original STRIP study, of whom 551 provided data at the age 26 years follow-up, and data for 507 participants were analysed (243 in the intervention group and 264 in the control group). At follow-up, those who had been in the intervention group had slightly lower mean intake of saturated fat as a proportion of total energy intake than the control group (13·0% [SD 3·3] vs 13·7% [3·6], p=0·049). A higher proportion of participants in the intervention group achieved the targeted monounsaturated and polyunsaturated fat to saturated fat ratio of more than 2:1 than the control group (78 [39%] of 200 vs 70 [30%] of 235; risk ratio [RR] 1·16 [95% CI 1·01-1·33]; p=0·035). A higher proportion of intervention group participants met the ideal total cholesterol concentration of less than 5·17 mmol/L (194 [81%] of 240 vs 187 [72%] of 261; RR 1·45 [1·05-2·01], p=0·024) and optimal LDL cholesterol concentration of less than 3·0 mmol/L (166 [69%] of 240 vs 158 [61%] of 251; RR 1·30 [1·03-1·66], p=0·031). Those who received the intervention had lower glucose (5·00 mmol/L [SD 0·43] vs 5·07 mmol/L [0·46], p=0·040) and HOMA-IR (median 1·44 [IQR 1·09-1·91] vs 1·62 [1·22-2·09], p=0·037) than the participants in the control group. INTERPRETATION: Previously observed intervention effects during the 20-year counselling were largely maintained into adulthood 6 years after the withdrawal of the intervention. Dietary counselling introduced in infancy thus provided a sustained benefit to diet quality and cardiometabolic risk factor levels. FUNDING: Academy of Finland, Juho Vainio Foundation, Finnish Foundation for Cardiovascular Research, Finnish Ministry of Education and Culture, Finnish Cultural Foundation, Sigrid Jusélius Foundation, Special Governmental grants for Health Sciences Research (Turku University Hospital), Yrjö Jahnsson Foundation, Finnish Medical Foundation, and Turku University Foundation.

Dietary Fats and Atherosclerosis From Childhood to Adulthood.

BACKGROUND: The association of dietary fat distribution with markers of subclinical atherosclerosis during early life is unknown. We examined whether success in achieving the main target of an infancy-onset dietary intervention based on the distribution of dietary fat was associated with aortic and carotid intima-media thickness (IMT) and distensibility from childhood to young adulthood. METHODS: In the prospective randomized controlled Special Turku Coronary Risk Factor Intervention Project trial, personalized dietary counseling was given biannually to healthy children from infancy to young adulthood. The counseling was based on Nordic Nutrition Recommendations, with the main aim of improving the distribution of dietary fat in children's diets. IMT and distensibility of the abdominal aorta and common carotid artery were measured repeatedly at ages 11 (n = 439), 13 (n = 499), 15 (n = 506), 17 (n = 477), and 19 years (n = 429). The targeted distribution of dietary fat was defined as a ratio of saturated fatty acids to monounsaturated and polyunsaturated fatty acids of <1:2 and as an intake of saturated fatty acids of <10% of energy intake. Participants who met ≥1 of these 2 criteria were defined to achieve the main intervention target. RESULTS: Individuals who achieved the main intervention target had lower aortic IMT (age- and sex-adjusted mean difference 10.4 µm; 95% confidence interval: 0.3 to 20.5 µm) and better aortic distensibility (0.13% per 10 mm Hg; 95% confidence interval: 0.00% to 0.26% per10 mm Hg) compared with their peers who did not meet the target. CONCLUSIONS: Achieving the main target of an infancy-onset dietary intervention, reflecting dietary guidelines, was favorably associated with aortic IMT and distensibility during the early life course. These data support the recommendation of favoring unsaturated fat to enhance arterial health.

Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies.

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.

Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children.

OBJECTIVE: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). RESULTS: A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. CONCLUSIONS: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches.

Serum 25-Hydroxyvitamin D Concentrations at Birth in Children Screened for HLA-DQB1 Conferred Risk for Type 1 Diabetes.

CONTEXT: Vitamin D has several effects on the immune system that might be of relevance for the pathogenesis of type 1 diabetes (T1D). OBJECTIVE: To evaluate whether umbilical cord serum concentrations of 25-hydroxy-vitamin D (25[OH]D) differ in children developing either islet autoimmunity (IA) or overt T1D during childhood and adolescence. DESIGN: Umbilical cord serum samples from 764 children born from 1994 to 2004 with HLA-DQB1 conferred risk for T1D participating in the Type 1 Diabetes Prediction and Prevention Study were analyzed for 25(OH)D using an enzyme immunoassay. SETTING: DIPP clinics in Turku, Oulu, and Tampere University Hospitals, Finland. PARTICIPANTS: Two hundred fifty children who developed T1D diabetes at a median age of 6.7 years (interquartile range [IQR] 4.0 to 10.1 years) and 132 additional case children who developed IA, i.e., positivity for multiple islet autoantibodies. Cases were matched for date of birth, gender, and area of birth with 382 control children who remained autoantibody negative. The median duration of follow up was 9.8 years (IQR 5.7 to 13.1 years). MAIN OUTCOME MEASURE: The median 25(OH)D concentrations. RESULTS: The median 25(OH)D concentration in cord serum was low [31.1 nmol/L (IQR 24.0 to 41.8); 88% <50 nmol/L], but not statistically different between children who developed T1D or IA and their control groups (P = 0.70). The levels were associated mainly with geographical location, year and month of birth, age of the mother, and maternal intake of vitamin D during pregnancy. CONCLUSIONS: The 25(OH)D concentrations at birth are not associated with the development of T1D during childhood.

Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study.

OBJECTIVE: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3 to 4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, human leukocyte antigen-DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included insulin autoantibodies (IAA) or glutamic acid decarboxylase (GADA) as the first appearing autoantibody. RESULTS: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio [HR] 1.11; 95% confidence interval [CI] 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. CONCLUSIONS: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy.

Longitudinal effect of 20-year infancy-onset dietary intervention on food consumption and nutrient intake: the randomized controlled STRIP study.

BACKGROUND/OBJECTIVES: Coronary heart disease begins in childhood and warrants prevention strategies such as dietary modification. The objective was to determine the effect of the Special Turku Coronary Risk Factor Intervention Project (STRIP) dietary intervention on food consumption and nutrient intake over 20-year intervention period. SUBJECTS/METHODS: The STRIP is a prospective, randomized trial conducted between 1990 and 2011. Enrolled 6-month-old infants (n = 1062) were randomized to an intervention group (n = 540) receiving dietary counseling biannually from age 7 months to 20 years or control group (n = 522) not receiving any intervention. Food and nutrient intake was assessed annually using 4-day food records. A food-based diet score was calculated. RESULTS: The intervention led to (1) higher consumption of low-fat unsweetened dairy (ß = 177.76, 95% CI 157.36-198.16 g/day), vegetable-oil based fats (ß = 6.00, 5.37-6.63 g/day), fish (ß = 2.45, 1.44-3.45 g/day), fiber-rich grain products (ß = 5.53, 3.17-7.89 g/day), fruits/berries (ß = 9.93, 4.44-15.43 g/day), vegetables (ß = 11.95, 7.74-16.16 g/day); (2) lower consumption of desserts (ß = - 4.10, 95% CI - 6.50 to - 1.70 g/day); (3) lower intake of sucrose (ß = - 1.61, 95% CI - 2.88 to - 0.35 g/day), and higher intake of fiber (ß = 0.83, 0.55-1.11 g/day), folate (ß = 11.14, 95% CI 8.23-14.05 µg/day), vitamin D (ß = 0.52, 0.39-0.64 µg/day), C (ß = 8.08, 4.79-11.38 mg/day), E (ß = 0.93, 0.81-1.05 mg/day), iron (ß = 0.31, 0.18-0.44 mg/day), zinc (ß = 0.29, 0.17-0.40 mg/day), magnesium (ß = 12.17, 9.02-15.33 mg/day), sodium (ß = 55.00, 24.40-85.60 mg/day), potassium (ß = 157.11, 107.24-206.98 mg/day). No effect was found on nut/seed, red/processed meat, sugar-sweetened beverage, salty snack consumption, or vitamin A and calcium intake. Intervention effect was more pronounced in boys. CONCLUSIONS: The STRIP intervention improved children's diet quality over 20 years, indicating that beneficial dietary changes can be introduced and sustained in youth.

Success in Achieving the Targets of the 20-Year Infancy-Onset Dietary Intervention: Association With Insulin Sensitivity and Serum Lipids.

OBJECTIVE: We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention associated with insulin sensitivity and serum lipids from early childhood to young adulthood. RESEARCH DESIGN AND METHODS: The sample comprised 941 children participating in the prospective, randomized Special Turku Coronary Risk Factor Intervention Project (STRIP). Dietary counseling was given biannually based on the Nordic Nutrition Recommendations with the main aim to improve the quality of dietary fat in children's diets and the secondary aim to promote intake of vegetables, fruits, and whole-grain products. Food records and serum lipid profile were studied annually from 1 to 20 years of age, and HOMA of insulin resistance (HOMA-IR) was assessed between 7 and 20 years of age. Meeting the intervention targets for quality of dietary fat was defined as the ratio of saturated fatty acids (SAFA) to monounsaturated and polyunsaturated fatty acids (MUFA + PUFA) <1:2 and intake of SAFA <10% of total energy intake (E%). Meeting the target for intake of whole-grain products, fruits, and vegetables was indicated by a fiber intake ≥3 g/MJ. RESULTS: Participants in the intervention group had a higher probability of meeting the targets of SAFA/(PUFA + MUFA) <1:2 (risk ratio [RR] 3.91 [95% CI 3.33-4.61]), intake of SAFA <10 E% (RR 3.33 [95% CI 2.99-3.96]), and intake of fiber >3 g/MJ (RR 1.37 [95% CI 1.04-1.80]). Participants who achieved more targets had lower HOMA-IR, lower concentrations of fasting serum glucose, insulin, LDL cholesterol, and non-HDL cholesterol, and a lower ratio of apolipoprotein (Apo) B/ApoA1 (P values all ≤0.003). CONCLUSIONS: Achieving the key targets of an infancy-onset 20-year dietary intervention was associated with better insulin sensitivity and serum lipid profile throughout the early life course.

Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies.

Context: A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective: To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants: A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure: The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results: A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions: The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

Early Infant Diet and Islet Autoimmunity in the TEDDY Study.

OBJECTIVE: To examine duration of breastfeeding and timing of complementary foods and risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes (T1D) in the U.S., Finland, Germany, and Sweden. This study included 7,563 children with at least 9 months of follow-up. Blood samples were collected every 3 months from birth to evaluate IA, defined as persistent, confirmed positive antibodies to insulin (IAAs), GAD, or insulinoma antigen-2. We examined the associations between diet and the risk of IA using Cox regression models adjusted for country, T1D family history, HLA genotype, sex, and early probiotic exposure. Additionally, we investigated martingale residuals and log-rank statistics to determine cut points for ages of dietary exposures. RESULTS: Later introduction of gluten was associated with increased risk of any IA and IAA. The hazard ratios (HRs) for every 1-month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively. Martingale residual analysis suggested that the age at gluten introduction could be grouped as <4, 4-9, and >9 months. The risk of IA associated with introducing gluten before 4 months of age was lower (HR 0.68; 95% CI 0.47, 0.99), and the risk of IA associated with introducing it later than the age of 9 months was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age. CONCLUSIONS: The timing of gluten-containing cereals and IA should be studied further.

Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident ß-cell autoantibodies.

ß-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing ß-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first ß-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing ß-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing ß-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged ≥2 years. Gestational infections were not associated with the first appearing ß-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing ß-cell autoantibody in early life.

Cesarean Section on the Risk of Celiac Disease in the Offspring: The Teddy Study.

OBJECTIVE: Cesarean section (C-section) is associated with various immune-mediated diseases in the offspring. We investigated the relationship between mode of delivery and celiac disease (CD) and CD autoimmunity (CDA) in a multinational birth cohort. METHODS: From 2004 to 2010, infants from the general population who tested positive for HLA DR3-DQ2 or DR4-DQ8 were enrolled in The Environmental Determinants for Diabetes in the Young (TEDDY) study. Children were annually screened for transglutaminase autoantibodies, if positive, they are retested after 3 to 6 months and those persistently positive defined as CDA. Associations of C-section with maternal (age, education level, parity, pre-pregnancy weight, diabetes, smoking, weight gain during pregnancy) and child characteristics (gestational age, birth weight) were examined by Fisher exact test or Wilcoxon rank-sum test. Hazard ratios (HRs) for CDA or CD were calculated by Cox proportional hazard regression models. RESULTS: Of 6087 analyzed singletons, 1600 (26%) were born by C-section (Germany 38%, United States 37%, Finland 18%, Sweden 16%), and the remaining were born vaginally without instrumental support; 979 (16%) had developed CDA and 343 (6%) developed CD. C-section was associated with lower risk for CDA (hazard ratio [HR] = 0.85; 95% confidence interval [CI] 0.73, 0.99 P = 0.032) and CD (HR = 0.75; 95% CI 0.58, 0.98; P = 0.034). After adjusting for country, sex, HLA-genotype, CD in family, maternal education, and breast-feeding duration, significance was lost for CDA (HR = 0.91; 95% CI 0.78, 1.06; P = 0.20) and CD (HR = 0.85; 95% CI 0.65, 1.11; P = 0.24). Presurgical ruptured membranes had no influence on CDA or CD development. CONCLUSION: C-section is not associated with increased risk for CDA or CD in the offspring.

Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children.

AIMS/HYPOTHESIS: During the A/H1N1 2009 (A/California/04/2009) pandemic, mass vaccination with a squalene-containing vaccine, Pandemrix®, was performed in Sweden and Finland. The vaccination was found to cause narcolepsy in children and young adults with the HLA-DQ 6.2 haplotype. The aim of this study was to investigate if exposure to Pandemrix® similarly increased the risk of islet autoimmunity or type 1 diabetes. METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, children are followed prospectively for the development of islet autoimmunity and type 1 diabetes. In October 2009, when the mass vaccination began, 3401 children at risk for islet autoimmunity and type 1 diabetes were followed in Sweden and Finland. Vaccinations were recorded and autoantibodies against insulin, GAD65 and insulinoma-associated protein 2 were ascertained quarterly before the age of 4 years and semi-annually thereafter. RESULTS: By 5 August 2010, 2413 of the 3401 (71%) children observed as at risk for an islet autoantibody or type 1 diabetes on 1 October 2009 had been vaccinated with Pandemrix®. By 31 July 2016, 232 children had at least one islet autoantibody before 10 years of age, 148 had multiple islet autoantibodies and 96 had developed type 1 diabetes. The risk of islet autoimmunity was not increased among vaccinated children. The HR (95% CI) for the appearance of at least one islet autoantibody was 0.75 (0.55, 1.03), at least two autoantibodies was 0.85 (0.57, 1.26) and type 1 diabetes was 0.67 (0.42, 1.07). In Finland, but not in Sweden, vaccinated children had a lower risk of islet autoimmunity (0.47 [0.29, 0.75]), multiple autoantibodies (0.50 [0.28, 0.90]) and type 1 diabetes (0.38 [0.20, 0.72]) compared with those who did not receive Pandemrix®. The analyses were adjusted for confounding factors. CONCLUSIONS/INTERPRETATION: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes.

Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity.

We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.

Correction to: Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study.

The authors regret that the SNP in SH2B3 was incorrectly referred to as rs3184505 instead of rs3184504 on both mentions in this paper (Methods section and Table 1).