Genetic and environmental modifiers of iron overload disease. Why do only some patients get serious health outcomes?

Type 1 genetic haemochromatosis causes iron overload and is most commonly caused by homozygosity for the HFE C282Y variant and to a far lesser extent other HFE C282Y and H63D genotypes. Haemochromatosis is one of the most common genetic conditions in populations of Northern European ancestry, with approximately 1 in 150 individuals carrying the high-risk C282Y homozygous genotype. However, its clinical expression is highly variable, and early symptoms typically present as general signs of ageing, including fatigue and joint pain. Haemochromatosis is therefore often misdiagnosed or diagnosed late. Fortunately, although the condition is lifelong, there is effective treatment available, typically in the form of periodic venesection. However, the overarching clinical challenge is identifying individuals in need of treatment prior to the development of iron overload-related complications. While research has shown that individuals may develop life-threatening iron overload-related complications, including liver disease, liver cancer, diabetes, and osteoarthritis, many remain unaffected throughout their lives. The determinants of this variable penetrance remain incompletely understood. This thesis investigates the genetic and lifestyle factors that modify the risk of haemochromatosis-related iron overload and associated clinical outcomes, using population-based data from the UK Biobank cohort with linked medical records, genetic data, and phenotypic data. Previous studies have reported low penetrance of the condition, with less than 1% of HFE C282Y homozygotes developing complications. However, more recent population-based studies have shown much higher penetrance than previously thought. To address this varied consensus on clinical penetrance in the literature, I first characterised the risks of several clinical outcomes across all HFE C282Y and H63D genotypes compared with individuals without HFE C282Y or H63D variants. I then examined how environmental and lifestyle factors including adiposity, alcohol intake, smoking, diet, and others influenced liver iron concentrations and disease expression. These analyses demonstrated that modifiable exposures substantially alter disease penetrance, particularly with respect to central adiposity and risk of liver outcomes. I then extended these investigations to genetic determinants beyond the HFE gene, showing that polygenic predisposition to elevated iron biomarkers, specifically higher transferrin saturation and serum iron, further exacerbates the risk of clinical manifestation among C282Y homozygotes. Moreover, I found rare loss-of-function variants within the HFE gene region that were associated with haemochromatosis while conditioning on the C282Y variant. The findings from my research provide evidence from a large generalisable community-based cohort of HFE-genotyped individuals, that both genetic and environmental/lifestyle factors influence the clinical expression of haemochromatosis and associated outcomes. By reporting absolute risks alongside relative effect estimates, my thesis offers clinically interpretable insights into which individuals are most likely to develop complications and highlights the potential for prevention through targeted lifestyle interventions and precision risk stratification.<p></p>

Author dc:creator

• Mitchell Lucas (7547369)

• Epidemiology
• Population health
• Haemochromatosis
• UK Biobank
• Genetic Epidemiology

Statement dc:rights

• All rights reserved

Identifier

10779/exe.32415597.v1

OAI identifier oai:identifier

oai:figshare.com:article/32415597