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

## TL;DR

The study maps genetic and clinical risk of hereditary haemochromatosis across the British Isles and Ireland, showing higher risk in Northwest Ireland and the Outer Hebrides.

## Contribution

The paper provides a detailed regional analysis of genetic risk and clinical diagnosis rates of haemochromatosis across 29 regions.

## Key findings

- Northwest Irish and Outer Hebrideans have the highest genetic risk of haemochromatosis (1/54 – 1/62).
- White Irish individuals have 3.7x higher clinical prevalence than white British.
- Genetic risk and clinical diagnosis rates show regional discrepancies, suggesting under-diagnosis in some areas.

## 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.

Here the authors analyse genetic data for over 400,000 British and Irish people, showing that the frequency of the major genetic risk factor for haemochromatosis varies from a low of 1/212 in Southern England to 1/62-1/54 in Outer Hebrideans and Northwest Irish. Clinically diagnosed haemochromatosis varies 11- fold in frequency across England, emphasising the uneven risk landscape.