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 HLADR3-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

Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study

Objective: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. however, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (cDa) in genetically predisposed children. Design: The environmental Determinants of Diabetes in the Young study prospectively followed children carrying the hla risk haplotypes DQ2 and/or DQ8 and constructed a nested case–control design. From this design, 83 cDa case–control pairs were identified. Median age of cDa was 31 months. stool samples collected monthly up to the age of 2 years were analysed for virome composition by illumina next-generation sequencing followed by comprehensive computational virus profiling. Results: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for cDa. in addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake. Conclusions: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of cDa. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of cDa.Peer reviewe

A combined risk score enhances prediction of type 1 diabetes among susceptible children

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordType 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational ScienceDiabetes Research CenterDiabetes UKWellcome TrustJDR

Neighborhood level risk factors for type 1 diabetes in youth: the SEARCH case-control study

<p>Abstract</p> <p>Background</p> <p>European ecologic studies suggest higher socioeconomic status is associated with higher incidence of type 1 diabetes. Using data from a case-control study of diabetes among racially/ethnically diverse youth in the United States (U.S.), we aimed to evaluate the independent impact of neighborhood characteristics on type 1 diabetes risk. Data were available for 507 youth with type 1 diabetes and 208 healthy controls aged 10-22 years recruited in South Carolina and Colorado in 2003-2006. Home addresses were used to identify Census tracts of residence. Neighborhood-level variables were obtained from 2000 U.S. Census. Multivariate generalized linear mixed models were applied.</p> <p>Results</p> <p>Controlling for individual risk factors (age, gender, race/ethnicity, infant feeding, birth weight, maternal age, number of household residents, parental education, income, state), higher neighborhood household income (p = 0.005), proportion of population in managerial jobs (p = 0.02), with at least high school education (p = 0.005), working outside the county (p = 0.04) and vehicle ownership (p = 0.03) were each independently associated with increased odds of type 1 diabetes. Conversely, higher percent minority population (p = 0.0003), income from social security (p = 0.002), proportion of crowded households (0.0497) and poverty (p = 0.008) were associated with a decreased odds.</p> <p>Conclusions</p> <p>Our study suggests that neighborhood characteristics related to greater affluence, occupation, and education are associated with higher type 1 diabetes risk. Further research is needed to understand mechanisms underlying the influence of neighborhood context.</p

Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study

A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65-0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01-1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05-2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43-0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75-5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes

Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Metabolite-related dietary patterns and the development of islet autoimmunity

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in theYoung) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts