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

IntroductionHFE 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. MethodsWe 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. ResultsMean 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 ({beta}=0.11, 95%CI: 0.09-0.11, p=6.0x10-128; >30 vs. 1-14 units/week), frequent red/processed meat consumption ({beta}=0.08, 95%CI: 0.07-0.09, p=3.7x10-54; [≥]3 times/week vs. none), high waist-height ratio ({beta}=0.01, 95%CI: 0.006-0.02, p=6.4x10-5) and genetically predicted transferrin saturation ({beta}=0.22, 95%CI: 0.19- 0.26, p=3.8x10-46). Lower MRLIC was associated with underweight BMI ({beta}=-0.06, 95%CI: -0.09 - -0.03, p=1.1x10-4), proton pump inhibitor use ({beta}=-0.03, 95%CI: -0.04 - -0.03, p=3.5x10-17), and [≥]4 cups/day of tea ({beta}=-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 ({beta}=-0.99, 95%CI: -1.89 - -0.08, p=0.03). ConclusionUndiagnosed 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.