Dietary heme iron intake and common hemochromatosis HFE polymorphisms have similar associations with brain MRI phenotypes: a UK Biobank cohort study

BACKGROUND: Brain iron accumulation is associated with aging and neurodegeneration, but how individual genetics and dietary iron intake affect brain iron is not well understood. Hemochromatosis is a genetic disorder arising from single nucleotide polymorphisms (SNPs) in the HFE gene, causing iron overload and brain iron accumulation, and is associated with accelerated brain aging. OBJECTIVE: This cross-sectional study examined how dietary iron intake and hemochromatosis-associated single nucleotide polymorphisms are associated with brain MRI phenotypes sensitive to iron. METHODS: We used a subset of the UK Biobank (N=24,223 participants) to investigate associations between dietary heme and non-heme iron intake (dietary predictors), HFE SNPs rs1799945 and rs1800562 (genetic predictors), brain quantitative susceptibility mapping (QSM) and T2* MRI phenotypes (primary outcomes) using multiple regression. We also investigated associations of HFE SNPs and dietary intake with hemoglobin, anemia risk, and MRI-derived liver iron levels as markers of systemic iron status. We compared brain QSM for rs1799945 and rs1800562 homozygotes and rs1799945/rs1800562 compound heterozygotes relative to control genotype subjects without either HFE SNP using ANCOVA and Tukey-Kramer post-hoc testing. Significance was set at false discovery rate (FDR) <0.05. RESULTS: Intake of dietary heme iron and both HFE SNPs were associated with increased QSM and decreased T2* MRI intensities (FDR<0.05), a pattern associated with increased brain iron levels. Non-heme iron intake was associated with a slight, but statistically significant, decrease in QSM and increase in T2* intensity, which is consistent with less brain iron. Both SNPs and heme iron intake were associated with higher hemoglobin and MRI-derived liver iron levels. Adjusted mean QSM intensity was generally highest for rs1800562 homozygotes and mostly higher in rs1799945 homozygotes and rs1799945/rs1800562 compound heterozygotes compared to control genotype. CONCLUSIONS: Dietary heme iron intake and SNPs linked to hemochromatosis are associated with altered brain MRI intensities consistent with elevated brain iron.