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 the Young) 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.
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.
Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without ( = 376) or with one or several IAs against insulin, GAD65, or IA-2 ( = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs.
Background High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. Objectives To investigate if different dietary gluten sources up to age two years confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. Design Three-day food records were collected at age six, nine, 12, 18 and 24 months from 2088 Swedish genetically at-risk children participating in a 15-year follow-up cohort study on type 1 diabetes and celiac disease. Screening for celiac disease was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated hazard ratios (HR) with 95% confidence intervals (CI) for daily intake of gluten sources. Results During follow-up, 487 (23.3%) children developed CDA, and 242 (11.6%) developed CD. Daily intake of ≤158 g porridge at age nine months was associated with increased risk of CDA (HR 1.53, 95% CI 1.05, 2.23, P = 0.026). A high daily bread intake (>18.3 g) at age 12 months was associated with increased risk of both CDA (HR 1.47, 95% CI 1.05, 2.05, P = 0.023) and CD (HR 1.79, 95% CI 1.10, 2.91, P = 0.019). At age 18 months, milk cereal drink was associated with an increased risk of CD (HR 1.16, 95% CI 1.00, 1.33, P = 0.047) per 200 g/day increased intake. No association was found for other gluten sources up to age 24 months and risk of CDA or CD. Conclusions A high daily intake of bread at age 12 months and milk cereal drink during the second year in life is associated with increased risk of both celiac disease autoimmunity and celiac disease in genetically at-risk children.
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