HFE genotypes, haemochromatosis diagnosis status and clinical penetrance to age 80 in the UK Biobank community cohort

Objectives: Type-1 haemochromatosis HFE genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort. Design: Prospective cohort study. Setting:22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010). Participants:451,270 participants genetically similar to the 1000-Genomes European reference population, with a mean 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data. Main outcome measures: Cox proportional hazard ratios of incident clinical outcomes and mortality in those with HFE p.C282Y-p.H63D mutations compared to those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 to 80 years. Results: 12.1% of p.C282Y+/+ males had baseline (mean age 57) haemochromatosis diagnoses, with age 80 cumulative incidence of 56.4%. 33.1% died vs. 25.4% without HFE variants (Hazard Ratio [HR] 1.29, 95% CI: 1.12-1.48, p=4.7*10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there was excess delirium, dementia, and Parkinsons disease, but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of p.C282Y+/+ females had baseline haemochromatosis diagnoses, with cumulative age 80 incidence of 40.5%. There was excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27-2.05, p=7.8*10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes. Conclusions: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the University of Exeter supports ML, LP and DM; JA has a National Institute for Health and Care Research (NIHR) Advanced Fellowship (NIHR301844). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript This research was conducted using the UK Biobank resource, under application 14631.