Liver iron levels are associated with HFE -hemochromatosis genotype, diet, adiposity, and disease in the UK Biobank
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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/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 analysed 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 2.31mg/g) vs. diagnosed (1.23 & 1.51mg/g, p=0.0001 & 0.0004). Other HFE genotypes had nominal increases vs. 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/week), 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 ) 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 BMI (β=−0.06, 95%CI: −0.09 – −0.03, p=1.1×10 −4 ), proton pump inhibitor use (β=−0.03, 95%CI: −0.04 – −0.03, p=3.5×10 −17 ), and ≥4 cups/day of tea (β=−0.01, 95%CI: −0.02 – −0.003, p=0.005 vs. non-drinkers). Among C282Y+/+ individuals (n=91), tea ≥4 cups/day was associated with lower MRLIC (β=−0.99, 95%CI: −1.89 – −0.08, p=0.03).
Conclusion
Undiagnosed C282Y+/+ individuals had excess liver iron vs. diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.
