Genetic and lifestyle modifiers of haemochromatosis-related clinical outcomes in HFE C282Y homozygotes

<h2>Abstract</h2><h3>Background & Aims</h3> The iron overload disease haemochromatosis is primarily caused by <i>HFE</i> p.C282Y homozygosity, yet penetrance of clinical outcomes (including liver disease/cancer) varies. We aimed to estimate the effect of genetic and lifestyle factors on disease penetrance and expressivity in <i>HFE</i> C282Y homozygotes. <h3>Methods</h3> We analysed 2,893 C282Y homozygous UK Biobank participants (n=1,295 male). We ascertained haemochromatosis from medical records, liver disease/cancer, osteoarthritis, joint replacement surgeries, and dementia diagnoses. We derived polygenic scores (PGS) for iron biomarkers including hepcidin and transferrin saturation (TSAT). Sex-stratified logistic regression assessed associations with clinical outcomes. We used time-to-event regression estimating effects of age, lifestyle, and PGS. We estimated effects of rare <i>HFE</i> variants using whole genome sequencing data. <h3>Results</h3> In male <i>HFE</i> C282Y homozygotes, higher TSAT PGS increased likelihood of diagnosis of haemochromatosis, and separately any clinical consequence (OR_{top-vs-bottom-PGS-quintile}=1.83, 95%CI: 1.26-2.66, p=0.001). Cumulative incidence of assessed haemochromatosis clinical outcomes in men by age 80 was 64.5% (highest quintile) versus 51.6% (lowest) (p-value for difference=0.025). In females, TSAT PGS increased haemochromatosis likelihood (cumulative incidence: 45.3% vs. 23.3% [highest/lower quintile], p=0.00001) but not liver disease. PGS for other iron biomarkers were not significantly associated with clinical outcomes. Rare heterozygous predicted loss-of-function variants in <i>HFE</i> increased haemochromatosis likelihood in non-C282Y homozygotes (aggregate-OR=14.8, 95%CI 4.7-41.1, p=0.003), highlighting the importance of sequencing undiagnosed individuals to find rare causes of haemochromatosis. <h3>Conclusion</h3> Higher genetically predicted transferrin saturation significantly increased risk of clinical outcomes in <i>HFE</i> C282Y homozygotes. Combined with modifiable lifestyle factors, genetic information could refine risk stratification and personalise iron monitoring, following validation.