Abstract
Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06–1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR = 1.05 [95%CI: 0.99–1.13] per 50 mg/L increase; soluble transferrin receptor: OR = 0.91 [95%CI: 0.81–1.01] per 0.5 mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.
Highlights
The rapid increase in incidence of type 1 diabetes (T1D) over the past 2–3 generations demonstrates the importance of yet unknown environmental factors[1,2]
Excess intestinal uptake of iron which occurs in hereditary hemochromatosis may lead to T1D, classically described as bronze diabetes, due to pancreatic iron accumulation[9]
Our findings suggest that excess prenatal iron may be a risk factor for T1D
Summary
The rapid increase in incidence of type 1 diabetes (T1D) over the past 2–3 generations demonstrates the importance of yet unknown environmental factors[1,2]. Common variants in the HFE gene (p.282Y and p.63D) are associated with cellular uptake of iron and hemochromatosis[10,11]. Both maternal and fetal HFE genotype likely influences fetal iron status[12]. In a large prospective study, we tested the hypothesis that iron supplements in pregnancy are associated with offspring risk of T1D. In smaller sub-studies we tested whether HFE genetic variants and cord plasma iron biomarkers are risk factors for childhood T1D. We assessed whether prenatal iron exposure predicted genome-wide fetal DNA methylation, maternal inflammatory cytokines, and gut microbiota, three factors hypothesised to mediate environmental influences on T1D risk (Fig. 1a). Our findings suggest that excess prenatal iron may be a risk factor for T1D
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