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

ObjectivesHFE haemochromatosis 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. DesignProspective cohort study. Setting22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010). Participants451,270 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 measuresCox 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. Results12.1% 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. ConclusionsMale 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. Strengths and limitations of this studyO_LIWe analyzed largescale data on community volunteers from the UK Biobank, one of the worlds largest HFE genotyped cohorts. C_LIO_LIWe have analyzed incident disease outcomes during an extended follow-up period of mean 13.3 years. C_LIO_LIWe have provided the first clinical outcome data to age 80 years in those with haemochromatosis genotypes, including those undiagnosed with haemochromatosis at baseline, expanding the life-course evidence on HFE penetrance. C_LIO_LIUK Biobank participants were somewhat healthier than the general population, but HFE allele frequencies were similar to previous UK studies. C_LIO_LIIncident outcomes were from hospital inpatient and cancer registry follow-up, so did not rely on potentially biased patient self-reporting, but community diagnosed conditions may be underestimated. C_LI