Prospective virome analyses in young children at increased genetic risk for type 1 diabetes.

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk.

Importance: High gluten intake during childhood may confer risk of celiac disease. Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study.

OBJECTIVE: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS: These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.

Maternal use of dietary supplements during pregnancy is not associated with coeliac disease in the offspring: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Perinatal exposure to nutrients and dietary components may affect the risk for coeliac disease (CD). We investigated the association between maternal use of vitamin D, n-3 fatty acids (FA) and Fe supplements during pregnancy and risk for CD autoimmunity (CDA) and CD in the offspring. Children at increased genetic risk were prospectively followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. CDA was defined as having persistently positive tissue transglutaminase autoantibodies (tTGA). Diagnosis of CD was either biopsy-confirmed or considered likely if having persistently elevated levels of tTGA>100 AU. Of 6627 enrolled children, 1136 developed CDA at a median 3·1 years of age (range 0·9-10) and 409 developed CD at a median 3·9 years of age (range 1·2-11). Use of supplements containing vitamin D, n-3 FA and Fe was recalled by 66, 17 and 94 % of mothers, respectively, at 3-4 months postpartum. The mean cumulative intake over the entire pregnancy was 2014 µg vitamin D (sd 2045 µg), 111 g n-3 FA (sd 303 g) and 8806 mg Fe (sd 7017 mg). After adjusting for country, child's human leucocyte antigen genotype, sex, family history of CD, any breast-feeding duration and household crowding, Cox's proportional hazard ratios did not suggest a statistically significant association between the intake of vitamin D, n-3 FA or Fe, and risk for CDA or CD. Dietary supplementation during pregnancy may help boost nutrient intake, but it is not likely to modify the risk for the disease in the offspring.

Factors associated with longitudinal food record compliance in a paediatric cohort study.

OBJECTIVE: Non-compliance with food record submission can induce bias in nutritional epidemiological analysis and make it difficult to draw inference from study findings. We examined the impact of demographic, lifestyle and psychosocial factors on such non-compliance during the first 3 years of participation in a multidisciplinary prospective paediatric study. DESIGN: The Environmental Determinants of Diabetes in the Young (TEDDY) study collects a 3 d food record quarterly during the first year of life and semi-annually thereafter. High compliance with food record completion was defined as the participating families submitting one or more days of food record at every scheduled clinic visit. SETTING: Three centres in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden). SUBJECTS: Families who finished the first 3 years of TEDDY participation (n 8096). RESULTS: High compliance was associated with having a single child, older maternal age, higher maternal education and father responding to study questionnaires. Families showing poor compliance were more likely to be living far from the study centres, from ethnic minority groups, living in a crowded household and not attending clinic visits regularly. Postpartum depression, maternal smoking behaviour and mother working outside the home were also independently associated with poor compliance. CONCLUSIONS: These findings identified specific groups for targeted strategies to encourage completion of food records, thereby reducing potential bias in multidisciplinary collaborative research.

Risk of pediatric celiac disease according to HLA haplotype and country.

BACKGROUND: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS: The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS: Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).