Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina’s NovaSeq 6000 was used to quantify gene expression in whole blood. With linear mixed models we tested for changes in expression after IA that differed across individuals who progressed to T1D (progressors) (n = 25), reverted to an autoantibody-negative stage (reverters) (n = 47), or maintained IA positivity but did not develop T1D (maintainers) (n = 66). Weighted gene coexpression network analysis was used to identify coexpression modules. Gene Ontology pathway analysis of the top 150 differentially expressed genes (nominal P < 0.01) identified significantly enriched pathways including leukocyte activation involved in immune response, innate immune response, and regulation of immune response. We identified a module of 14 coexpressed genes with roles in the innate immunity. The hub gene, LTF, is known to have immunomodulatory properties. Another gene within the module, CAMP, is potentially relevant based on its role in promoting β-cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D.

We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood. We measured DNA methylation in peripheral blood collected in infancy (9–15 months of age) in 243 children; and in a subset of 50 children, we also measured methylation in childhood (6–9 years of age) to examine persistence, and at birth (in cord blood) to examine temporality. We performed multivariable linear regression of infant diet on the outcome of methylation using epigenome-wide and candidate site approaches. We identified six novel CpG sites associated with breastfeeding duration using an EWAS approach. One differentially methylated site presented directionally consistent associations with breastfeeding (cg00574958, CPT1A) in infancy and childhood but not at birth. Two differentially methylated sites in infancy (cg19693031, TXNIP; cg23307264, KHSRP) were associated with breastfeeding and were not present at birth; however, these associations did not persist into childhood. Associations between infant diet and methylation in infancy at three sites (cg22369607, AP001525.1; cg2409200, TBCD; cg27173510, PGBD5) were also present at birth, suggesting the influence of exposures other than infant diet. Infant diet exposures are associated with persistent methylation differences in CPT1A, which may be one mechanism behind infant diet’s long-term health effects.

Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study (n = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D. The oxylipin profiles (adjusted for genetic predictors) were the response variables. The nutrient patterns were tested in the case-control study (n = 69 T1D cases, 69 controls), then validated in the DAISY cohort using a joint Cox proportional hazards model (n = 1933, including 81 T1D cases). The first nutrient pattern (NP1) was characterized by low beta cryptoxanthin, flavanone, vitamin C, total sugars and iron, and high lycopene, anthocyanidins, linoleic acid and sodium. After adjusting for T1D family history, the HLA genotype, sex and race/ethnicity, NP1 was associated with a lower risk of T1D in the nested case-control study (OR: 0.44, p = 0.0126). NP1 was not associated with the risk of T1D (HR: 0.54, p-value = 0.1829) in the full DAISY cohort. Future studies are needed to confirm the nested case-control findings and investigate the modifiable factors for oxylipins.

Context: Increased levels of 25-hydroxyvitamin D (25OHD) have been protective against islet autoimmunity (IA), a preclinical type 1 diabetes (T1D) disease state. However, the role of 25OHD and downstream metabolites in progression from IA to T1D is not well understood. Objective: We hypothesized that downstream vitamin D metabolites and metabolite ratios would be associated with progression from IA to T1D. Methods: Among participants at high genetic risk for T1D who developed IA (n = 143) in the Diabetes Autoimmunity Study in the Young (DAISY), a T1D birth cohort study, we quantified vitamin D3, 25OHD2, 3-epi-25OHD3, 25OHD3, 24,25(OH)2D3, and 1α,25(OH)2D3 metabolites from plasma samples using LC-MS/MS. We calculated the vitamin D metabolite ratio (VMR) (ie, 24,25(OH)2D3/25OHD3) and the epimer ratio (3-epi-25OHD3/25OHD3). We also tested the correlation between metabolite levels and gene expression in a subset of participants (n = 53). Results: A total of 57/143 progressed to T1D. Higher VMR (hazard ratio (HR) per 1 SD increase: 0.65; 95% CI: 0.49-0.88) and levels of 24,25(OH)2D3 (HR per 1 SD increase: 0.72; 95% CI: 0.55-0.94) at IA seroconversion were associated with a lower risk of progression to T1D, adjusting for seroconversion age, season, HLA-DR3/4 genotype, and ancestry. Functional enrichment analysis suggests higher VMR resulted in a gene expression pattern in whole blood characteristic of decreased activation of inflammatory pathways related to neutrophil infiltration. Conclusion: A higher VMR, a more functional measure of vitamin D status, was protective against T1D progression, perhaps by decreasing activation of inflammatory pathways.