The landscape of hereditary haemochromatosis risk and diagnosis across the British Isles and Ireland

Abstract

Abstract Hereditary haemochromatosis is caused by pathogenic variants in the homoeostatic iron regulator gene HFE . Outcomes include liver cancer, cirrhosis and arthropathy, but penetrance is incomplete. Here, we use genetic data from >400,000 subjects to determine the genetic risk across 29 regions of the British Isles and Ireland. Northwest Irish and Outer Hebrideans are at the highest risk (1/54 – 1/62 carry the major risk genotype), Mainland Scots are also at increased risk (1/117), declining to 1/212 in Southern England. We also assessed the prevalence of clinically diagnosed haemochromatosis in >63 million people in NHS England and identified 70,365 cases. White Irish individuals have the highest prevalence (3.7x white British). Among white British, prevalence varied 11-fold from 1/1972 in parts of Kent to 1/177 in Liverpool. Discrepancies between genetic risks and prevalences of clinical diagnoses for Birmingham, Cumbria, Northumberland and Durham suggest under-diagnosis in these regions. We show heightened genetic risk of haemochromatosis in people of Northwest Irish and Hebridean ancestry and suggest health-economic modelling of community screening should be targeted to these priority areas.