# Genetic and lifestyle modifiers of haemochromatosis-related clinical outcomes in HFE C282Y homozygotes

## TL;DR

The study finds that genetic factors like higher transferrin saturation polygenic scores increase clinical risks in people with a specific hemochromatosis mutation.

## Contribution

The study introduces polygenic scores for iron biomarkers as a novel tool to predict clinical outcomes in HFE C282Y homozygotes.

## Key findings

- Higher TSAT polygenic scores increased hemochromatosis diagnosis likelihood in men and women.
- Rare HFE variants increased hemochromatosis risk in non-C282Y homozygotes.
- Combining genetic and lifestyle factors improved prediction accuracy for clinical outcomes.

## Abstract

The iron overload disease haemochromatosis is primarily caused by HFE p.C282Y homozygosity, yet penetrance of clinical outcomes (including liver disease/cancer) varies. We aimed to estimate the effect of genetic and lifestyle factors on disease penetrance and expressivity in HFE C282Y homozygotes.

We analysed 2,893 C282Y homozygous UK Biobank participants (n = 1,295 male). We ascertained haemochromatosis from medical records, liver disease/cancer, osteoarthritis, joint replacement surgeries, and dementia diagnoses. We derived polygenic scores (PGS) for iron biomarkers, including hepcidin and transferrin saturation (TSAT). Sex-stratified logistic regression assessed associations with clinical outcomes. We used time-to-event regression estimating effects of age, lifestyle, and PGS, and estimated effects of rare HFE variants using whole-genome sequencing data.

In male HFE C282Y homozygotes, higher TSAT PGS increased the likelihood of diagnosis of haemochromatosis, and separately any clinical consequence (odds ratio [OR]top-vs-bottom-PGS-quintile = 1.83, 95% CI: 1.26–2.66, p = 0.001). Cumulative incidence of assessed haemochromatosis clinical outcomes in men by age 80 years was 64.5% (highest quintile) vs. 51.6% (lowest) (p for difference = 0.025). In women, TSAT PGS increased haemochromatosis likelihood (cumulative incidence: 45.3% vs. 23.3% [highest/lower quintile], p = 0.00001) but not liver disease. PGS for other iron biomarkers was not significantly associated with clinical outcomes. Rare heterozygous predicted loss-of-function variants in HFE increased haemochromatosis likelihood in non-C282Y homozygotes (aggregate OR = 14.8, 95% CI 4.7–41.1, p = 0.003), highlighting the importance of sequencing undiagnosed individuals to find rare causes of haemochromatosis.

Higher genetically predicted TSAT significantly increased risk of clinical outcomes in HFE C282Y homozygotes. Combined with modifiable lifestyle factors, genetic information could refine risk stratification and personalise iron monitoring, following validation.

There is a pressing clinical need to understand the wide variation in clinical outcomes observed in HFE C282Y homozygotes. Higher genetically predicted TSAT significantly increased the risk of clinical outcomes, including liver and musculoskeletal complications, in HFE C282Y homozygotes, highlighting non-HFE genetic influence on disease penetrance. These results are relevant for physicians and researchers, because combining genetic factors (TSAT PGS) with demographic and lifestyle factors provided the highest prediction accuracy for haemochromatosis and related clinical outcomes. Practically, integrating polygenic risk assessments with existing patient care pathways could enhance precision therapies by enabling the earlier, targeted management of high-risk HFE C282Y homozygotes, although external validation of these predictive models is required before clinical adoption.

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•There is a pressing clinical need to understand the wide variation in clinical outcomes observed in HFE C282Y homozygotes.•Higher genetically predicted TSAT increased liver and musculoskeletal risks, highlighting non-HFE genetic influence on disease penetrance.•Combining TSAT PGS with demographic and lifestyle factors gave the highest predictive accuracy.•Polygenic risk may enable earlier targeted care, but external validation is required before clinical adoption.

There is a pressing clinical need to understand the wide variation in clinical outcomes observed in HFE C282Y homozygotes.

Higher genetically predicted TSAT increased liver and musculoskeletal risks, highlighting non-HFE genetic influence on disease penetrance.

Combining TSAT PGS with demographic and lifestyle factors gave the highest predictive accuracy.

Polygenic risk may enable earlier targeted care, but external validation is required before clinical adoption.