GENETIC VARIATION, IRON AND LATER LIFE HEALTH OUTCOMES

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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.