HAEMOCHROMATOSIS HFE GENOTYPES AND CLINICAL PENETRANCE TO OUTCOMES: LESSONS FROM THE UK BIOBANK

Janice ATKINS¹, Luke C PILLING¹, Mitchell R LUCAS¹, Lucy R BANFIELD², Karen KNAPP², Jeremy D SHEARMAN³, David MELZER¹

¹Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
²The Department of Health and Care Professions, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
³Department of Gastroenterology, South Warwickshire University NHS Foundation Trust, Warwick, United Kingdom

Background:In European ancestry populations, HFE genetic variants can cause iron overload and haemochromatosis, especially in p.C282Y homozygous (+/+) males. Clinical penetrance to disease in older ages is unclear. We used UK Biobank data to provide new life-course insights into morbidity within p.C282Y/p.H63D genotypes.

Methods:UK Biobank European genetic ancestry participants (n~451,000, 39-73 years) were followed-up for mean 13.3 years. Cox proportional hazards models assessed associations between HFE genotypes (p.C282Y/p.H63D) and incident outcomes. Analyses were stratified by sex and adjusted for age, genetic principal components, and assessment centre.

Results:2,902 participants were p.C282Y+/+ (0.6%). Male p.C282Y+/+ had increased risk of mortality (HR=1.29, 95% CI:1.12-1.48, p=4.7*10-4; cumulative incidence 33.1% by age 80 compared to 25.4% without HFE variants), liver disease (HR=2.56, 95% CI:2.10-3.12, p=8.70*10-21) and liver cancer (HR=7.90, 95% CI:5.46-11.43, p=5.50*10-28) compared to those without variants. Other non-HFE genetic variants also affected penetrance to liver disease/liver cancer. Male p.C282Y+/+ also had increased risk of prostate cancer (but not other cancers), joint replacement, Parkinson’s disease, delirium, and dementia (HR=1.72, 95% CI:1.26-2.35, p=0.001; and higher brain iron deposition in magnetic resonance imaging), compared to those without variants.

Female p.C282Y+/+ had more modest excess morbidity, with no increased risk of menstrual problems, but increased risk of liver disease (HR=1.62, 95% CI:1.27-2.05, p=7.8*10-5) and joint replacement, especially post-menopause.

Conclusion:In this large community genotyped sample, male p.C282Y+/+, and to a lesser extent female p.C282Y+/+ was associated with substantial excess morbidity. There may be justification for targeted or community genotyping to identify haemochromatosis risks early in p.C282Y homozygotes.