Liver iron levels are associated with HFE-hemochromatosis genotype, diet, adiposity, and disease in the UK Biobank

INTRODUCTION: HFE genetic variants, especially C282Y homozygosity (C282Y+/+), can increase systemic iron and cause hemochromatosis, though expression varies. Excess iron can lead to liver disease and liver cancer, yet factors influencing liver iron beyond HFE genotype remain unclear. We investigated genetic/environmental factors influencing liver iron, including HFE genotype and hemochromatosis diagnosis. METHODS: We analyzed 37,287 European ancestry UK Biobank participants (mean age 64.1, SD: 7.6) with HFE genotypes and MRI-estimated liver iron concentrations (MRLIC). Linear regression assessed MRLIC associations with genetic and environmental factors, adjusting for age, sex, and genetic covariates. RESULTS: Mean MRLIC was highest in undiagnosed C282Y+/+ males and females (2.56 and 2.31 mg/g) versus diagnosed (1.23 and 1.51 mg/g, p=0.0001 and 0.0004). Other HFE genotypes had nominal increases versus those without HFE genetic variants. Higher MRLIC was associated with higher alcohol intake (β=0.11, 95% CI: 0.09-0.11, p=6.0×10-128; >30 vs. 1-14 units/wk), frequent red/processed meat consumption (β=0.08, 95% CI: 0.07-0.09, p=3.7×10-54; ≥3 times/week vs. none), high waist-height ratio (β=0.01, 95% CI: 0.006-0.02, p=6.4×10-5; although magnitude was weak) and genetically predicted transferrin saturation (β=0.22, 95% CI: 0.19-0.26, p=3.8×10-46). Lower MRLIC was associated with underweight body mass index (β=-0.06, 95% CI: -0.09 to -0.03, p=1.1×10-4) and proton pump inhibitor use (β=-0.03, 95% CI: -0.04 to -0.03, p=3.5×10-17). CONCLUSIONS: Undiagnosed C282Y+/+ individuals had excess liver iron versus diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.