Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload: Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study.

OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes.

Association between Neonatal Whole Blood Iron Content and Cytokines, Adipokines, and Other Immune Response Proteins.

(1) Background: High iron associates with inflammation and type 1 diabetes (T1D). Iron is essential not only for neonatal development but also for infectious microorganisms. The neonatal immune system is immature, and innate immunity prevails before immunocompetence develops. (2) Methods: In 398 newborns from the Danish Newborn Screening Biobank, we examined if whole blood iron (WB-Iron) content were associated with cytokines, adipokines, C-reactive protein (CRP), and mannose-binding lectin (MBL) in non-infected healthy neonates, and if these associations differed in newborns who later developed T1D (cases) (n = 199). WB-Iron was quantified using laser ablation inductively coupled plasma mass spectrometry on the neonatal dried blood spots. For each analyte, the relative change (RC) in the mean level was modeled by robust log-normal regression. (3) Results: A one unit increase in neonatal WB-Iron was associated with a 38% decrease in mean interleukin (IL)-6 levels (0.62; 95% CI: 0.40⁻0.95, p = 0.03), and a 37% decrease in mean MBL levels (0.63; 95% CI: 0.41⁻0.95, p = 0.03), but was not statistically significant after correction for multiple testing. (4) Conclusions: In summary, we found that higher neonatal WB-iron content was inversely associated with IL-6 and MBL, which may increase susceptibility to infections.

The Role of Iron in Type 1 Diabetes Etiology: A Systematic Review of New Evidence on a Long-Standing Mystery.

BACKGROUND: The incidence of type 1 diabetes (T1D) is rising, which might be due to the influence of environmental factors. Biological and epidemiological evidence has shown that excess iron is associated with beta-cell damage and impaired insulin secretion. AIM: In this review, our aim was to assess the association between iron and the risk of T1D. METHODS: A systematic literature search was performed in PubMed and EMBASE in July 2016. Studies investigating the effect of iron status/intake on the risk of developing T1D later were included, and study quality was evaluated. The results have been summarized in narrative form. RESULTS: From a total of 931 studies screened, we included 4 observational studies evaluating iron intake from drinking water or food during early life and the risk of T1D. The quality of the studies was moderate to high assessed via the nine-star Newcastle Ottawa Scale. One out of the four studies included in this review found estimates of dietary iron intake to be associated with risk of T1D development, whereas three studies found no such relationship for estimates of iron in drinking water. CONCLUSIONS: The limited number of studies included found dietary iron, but not iron in drinking water, to be associated with risk of T1D. Further studies are needed to clarify the association between iron and risk of T1D, especially studies including measurements of body iron status.

Neonatal levels of adiponectin, interleukin-10 and interleukin-12 are associated with the risk of developing type 1 diabetes in childhood and adolescence: A nationwide Danish case-control study.

BACKGROUND/AIM: An in-depth understanding of the early phase of type 1 diabetes (T1D) pathogenesis is important for targeting primary prevention. We examined if 14 preselected mediators of immune responses differed in neonates that later developed T1D compared to control neonates. METHODS: The study is a case-control study with a 1:2 matching. The individuals were born between 1981 through 2002. Cases were validated using the National Patient Register and the Danish Childhood Diabetes Register. Interleukin(IL)-1ß, IL-4, IL-6, IL-8, IL-10, IL-12p70, interferon gamma, tumor necrosis factor alpha, transforming growth factor beta 1 (active form), leptin, adiponectin, c-reactive protein, mannose-binding lectin and soluble triggering receptor expressed on myeloid cells-1 were measured by using a flowmetric Luminex xMAP® technology. We tested two models both including a number of possible confounders. In the first model (model 1) we also adjusted for HLA-DQB1 genotype. A total of 1930 groups of assay-matched cases and controls (4746 individuals) were included in the statistical analyses. RESULTS: Adiponectin was negatively associated with later risk of T1D in both models (relative change (RC), model 1: 0.95, P=0.046 and model 2: 0.95, P=0.006). IL-10 and IL-12 were both positively associated with T1D risk in the model 2 (RC, 1.19, P=0.006 and 1.07, P=0.02, respectively)-these results were borderline significant in model 1, but showed the same direction as the results from model 2. CONCLUSIONS: Our results indicate that specific immunological signatures are already present at time of birth in children developing T1D before the age of 18years.

Levels of soluble TREM-1 in children with newly diagnosed type 1 diabetes and their siblings without type 1 diabetes: a Danish case-control study.

BACKGROUND: Type 1 diabetes (T1D) is an organ-specific autoimmune disease with an increase in incidence worldwide including Denmark. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses and has been linked to autoimmunity, severe psychiatric disorders, sepsis, and cancer. HYPOTHESIS: Our primary hypothesis was that levels of soluble TREM-1 (sTREM-1) differed between newly diagnosed children with T1D and their siblings without T1D. METHODS: Since 1996, the Danish Childhood Diabetes Register has collected data on all patients who have developed T1D before the age of 18 years. Four hundred and eighty-one patients and 478 siblings with measurements of sTREM-1-blood samples were taken within 3 months after onset-were available for statistical analyses. Sample period was from 1997 through 2005. A robust log-normal regression model was used, which takes into account that measurements are left censored and accounts for correlation within siblings from the same family. RESULTS: In the multiple regression model (case status, gender, age, HLA-risk, season, and period of sampling), levels of sTREM-1 were found to be significantly higher in patients (relative change [95%CI], 1.5 [1.1; 2.2],P = 0.02), but after adjustment for multiple testing our result was no longer statistically significant (P adjust = 0.1). We observed a statistical significant temporal increase in levels of sTREM-1. CONCLUSION: Our results need to be replicated by independent studies, but our study suggests that the TREM-1 pathway may have a role in T1D pathogenesis.

Perinatal vitamin D levels are not associated with later risk of developing pediatric-onset inflammatory bowel disease: a Danish case-cohort study.

Objective Basic and epidemiologic studies on inflammatory bowel disease (IBD) have suggested an association between vitamin D and IBD risk. Though, the literature on IBD - especially pediatric-onset IBD - and vitamin D is still in its cradle. We therefore wanted to examine if levels of 25(OH)D at birth were associated with increased risk of developing pediatric-onset IBD. Material and methods A case-cohort study composed of cases diagnosed with Crohn's disease, ulcerative colitis or indeterminate/unclassified colitis and healthy controls. Cases and controls were matched on date of birth and were born in the period 1981-2004. Cases were diagnosed before the age of 18 years. The concentration of 25(OH)D was assessed from neonatal dried blood spots using a highly sensitive liquid chromatography tandem mass spectrometry. Odds ratios (OR) were calculated using conditional logistic regression and two-way ANOVA were used to test for season and birth year 25(OH)D variations. A total of 384 matched pairs were included in the statistical analyses. Results No significant association were found between levels of 25(OH)D and IBD risk in the adjusted model (OR [95% CI] (per 25 nmol/L increase), 1.12 [0.88; 1.42], p = 0.35). 25(OH)D levels were found to fluctuate significantly with season (p < 0.001) and year (p < 0.001). Median/Q1-Q3 values for 25(OH)D were 27.1/16.5-39.5 nmol/L for cases and 25.7/16.1-39.4 nmol/L for controls. Conclusion Our study do not suggest that a window of vulnerability exist around time of birth in regards to 25(OH)D levels and later pediatric-onset IBD risk.