Lead Research Organisation: University of Exeter
Department Name: Institute of Biomed & Clinical Science


Iron is an essential element but is also toxic. High iron levels have been linked to many disease processes, including dementia and other neurological disorders, liver and other cancers, arthritis, and diabetes, but whether iron actually causes all these conditions is still unclear. Iron levels are tightly controlled in the human body, but several common genetic variants have been identified that increase iron levels. These provide powerful tools for studying the effects of varying iron levels on human disease. As proven treatments already exist for correcting iron levels, clarifying the role of iron in disease could lead to better prevention and care for patients.
Iron related variants are drivers of the iron overload disease haemochromatosis: Britain and Ireland have the highest rates in the world of the main mutation causing hereditary haemochromatosis. Approximately 1 in 150 people of European descent in the UK (0.6%) are homozygous for the highest risk HFE C282Y variant. The MRC supported UK Biobank (UKB) has the largest number of HFE C282Y homozygote people thus far studied. We recently showed that C282Y homozygotes reported high rates of fatigue, diabetes, arthritis and liver disease in the baseline interview. In UKB we found that nearly 1.6% of people who had hip replacements were C282Y homozygotes, indicating that the associated joint problems can be severe. We also found, for the first time, that C282Y is associated with muscle loss with advancing age. Our pilot analyses showed a doubling of dementia diagnoses with C282Y, plus evidence of iron deposition in the UK Biobank brain scans. After excluding HFE C282Y, the other iron related genetic variants together are also associated with several conditions in the 60+ year olds. Numbers of new disease onsets over time are increasing rapidly in UK Biobank, so we now need to follow-up this work in the new clinical data being collected, plus the growing numbers with imaging data, to establish the true effects of the C282Y and other iron related mutations.
There are established treatments to lower iron levels including donating blood, although some clinical features of haemochromatosis are resistant to treatments if started too late. Understanding the effects of genetic differences between people in iron metabolism offers a rare opportunity to guide precision prevention, diagnosis and treatment for relatively common disabling conditions, perhaps including some cases of dementia.
We hypothesise that the combination of iron related variants could result in substantial risk of disease from iron overload, especially in older men and women. As iron levels are reduced by menstruation, we hypothesise that women with a genetic susceptibility to iron overload may increasingly develop clinical disease as they age past menopause. We also hypothesise that factors such as high alcohol intakes may increase the burden of disease from iron, and that the combination of haemochromatosis and the Alzheimer's disease associated ApoE variant may be particularly damaging to the brain.
In this proposal we seek support to characterise the mid and later-life health effects of iron related genetic variation. We plan to use the world leading data from the UK Biobank cohort, plus the Canadian Longitudinal Study of Aging and the US Health and Retirement Study. UK Biobank is due to release new data from the lengthening clinical follow-ups (soon up to 14 years after baseline), blood assays, imaging and survival. We aim to analyse data from the three cohorts and clarify the effects of genetically influenced variation in iron levels on human health, especially at older ages. The project will therefore be a cost-effective use of the large investment already made in UK Biobank and other genotyped cohorts.

Technical Summary

Iron is an essential element in many physiological processes, but it is also toxic. Iron is tightly regulated, but several common genetic variants alter iron levels in humans. High iron levels have been linked to many conditions, including dementia and certain cancers, but whether iron plays a causal role in each of the linked conditions is unclear.

Iron related variants are central to hereditary haemochromatosis. Our work in UK Biobank 40 to 70 year olds identified high prevalence of diabetes, arthritis and liver disease with the highest risk homozygous HFE C282Y variant. We also found strong associations with osteoporosis, polymyalgia rheumatica, muscle loss, chronic pain and frailty in the older group. After excluding HFE C282Y, the other iron variants together were also associated with several phenotypes in the 60+ year olds. However, data on incident disease are limited in the current UK Biobank data release.

We aim to test hypotheses that HFE variants are associated with substantial excess morbidity especially with advancing age, and that iron related variants are risk factors in dementia and common cancers. We also hypothesise that environmental exposures and gene-gene interactions with non-iron variants may increase the burden of disease. Given that iron overload is preventable and treatable, the answers could lead directly to changes in clinical care.

Genetic variants can produce evidence for likely causal links to health outcomes, with much reduced confounding and no reverse causation. We seek support to characterise the mid and later-life health effects of iron related genetic variation, especially in women and at older ages. We will mainly use UK Biobank (n=480,000 genotyped), plus the Canadian Longitudinal study on Aging (n=20,000) and the US Health and Retirement study (n=20,000). We seek to analyse data with longer follow-ups and more incident disease, blood assays, imaging and mortality data.

Planned Impact

If our project confirms and extends our pilot findings, our results are likely to have direct impact on the prevention and treatment of people with Hereditary Haemochromatosis (HH). The UK has one of the highest rates in the world of this condition, so our results should be of great practical importance to the NHS. Current evidence internationally is that most patients with HH are only diagnosed late in the clinical course, when substantial irreversible damage has already been done. Prevention of clinical morbidity and treatment for the great majority of patients with HH is well established, with simple phlebotomy being effective at reducing iron overload and many of the clinical manifestations in most patients. Given that phlebotomy is relatively cheap, effective and largely adverse event free, evidence of substantial excess morbidity from this most common of genetic disorders could lead to relatively quick implementation of services to identify and treat these patients early. Our project may therefore result in reductions in avoidable morbidity within the medium term.

In UK Biobank, the homozygous haemochromatosis HFE C282Y mutation was associated with a large excess of liver disease and cancer, 1.6% of all hip replacements and with a doubling of NHS hospital admissions, so early identification and preventive treatment could result in major healthcare savings.

Our preliminary data suggested strong novel associations between C282Y and sarcopenia, chronic pain and frailty in older people. Iron overload also occurs in dementia, with several current trials of iron chelators to prevent dementia already underway, although not targeted on those with iron increasing genetic variants. Our results could therefore inform precision approaches to preventing and treating major disabling conditions of later life. Excess frailty and dementia could be contributing to very large long-term care expenditures. When the PI presented the pilot work to the Connecticut State Insurer, there was great interest in whether early detection and treatment could reduce long term care costs. The PI is also in discussions with clinicians in the UK and in Connecticut about undertaking pilot clinical studies to confirm the UK Biobank findings and clarify the issues involved in improving clinical outcomes.

A recent economic appraisal of screening or early detection of haemochromatosis in Australia suggested that these strategies would be highly cost-effective, even on the cautious estimates used of penetrance to disease. If our pilot work is confirmed, it is likely that screening or early case finding would be even more cost-effective.

Using genetic variants for analyses, this project will provide estimates of effect with minimal confounding and no reverse causation, as the data available will support valid application of genetic epidemiology approaches including Mendelian randomization. This could help clarify the potential for iron related treatments of several common cancers and neurological conditions.
Description Collaboration with research leaders in Haemochromatosis, Lawrie Powell, Greg Anderson & Grant Ramm 
Organisation QIMR Berghofer Medical Research Institute
Country Australia 
Sector Academic/University 
PI Contribution MY MRC supported Haemochromatosis analyses in UK Biobank have taken forward the pioneering work started by Professor Powell and colleagues.
Collaborator Contribution Pilot analysis of early treatment outcomes, to clarify benefits of early treatment
Impact not yet
Start Year 2019
Description Collaboration with research leaders in Haemochromatosis, Paul Adams (Canada) 
Organisation Western University
Country Canada 
Sector Academic/University 
PI Contribution Prof Paul Adams led the previous largest study of the hemochromatosis mutation - the HEIRS study
Collaborator Contribution Prof Adams advised on our paper on liver cancer, published in JAMA (Atkins et al, 2020)
Impact . 2020 Nov 24;324(20):2048-2057. doi: 10.1001/jama.2020.21566. Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy
Start Year 2020