GENETIC VARIATION, IRON AND LATER LIFE HEALTH OUTCOMES

铁是一种必需元素，但也是有毒的。高铁水平与许多疾病过程有关，包括痴呆症和其他神经疾病、肝癌和其他癌症、关节炎和糖尿病，但铁是否真的导致了所有这些疾病仍不清楚。铁的水平在人体内受到严格控制，但已发现几种常见的基因变异会增加铁的水平。这些研究为研究不同铁水平对人类疾病的影响提供了强大的工具。由于已经存在纠正铁水平的已被证实的治疗方法，澄清铁在疾病中的作用可能会导致更好地预防和护理患者。铁相关变异是铁超载疾病血色素沉着症的驱动因素：英国和爱尔兰是世界上导致遗传性血色素沉着症的主要突变发生率最高的国家。在英国，大约每150名欧洲人后裔中就有1人(0.6%)是风险最高的HFE C282Y变异的纯合子。MRC支持的英国生物库(UKB)是迄今为止研究过的HFE C282Y纯合子人数最多的组织。我们最近发现，在基线访谈中，C282Y纯合子报告了疲劳、糖尿病、关节炎和肝病的高发病率。在UKB，我们发现接受髋关节置换的人中有近1.6%是C282Y纯合子，这表明相关的关节问题可能会很严重。我们还首次发现，随着年龄的增长，C282Y与肌肉损失有关。我们的试点分析显示，使用C282Y诊断痴呆症的人数翻了一番，再加上英国生物库大脑扫描中有铁沉积的证据。在排除了HFE C282Y之后，其他与铁相关的基因变异一起也与60岁以上的几种疾病有关。随着时间的推移，英国生物库中的新疾病发病数量正在迅速增加，因此我们现在需要在收集的新临床数据中跟踪这项工作，加上不断增长的成像数据，以确定C282Y和其他铁相关突变的真实影响。已经有了包括献血在内的降低铁水平的既定治疗方法，尽管血色素沉着症的一些临床特征如果开始太晚会对治疗产生抵抗力。了解人与人之间的遗传差异对铁代谢的影响，为指导相对常见的致残性疾病的精确预防、诊断和治疗提供了难得的机会，可能包括一些痴呆症病例。我们假设，铁相关变异的组合可能会导致铁超载导致疾病的巨大风险，特别是在老年男性和女性中。由于铁水平会因月经而降低，我们假设，铁超载的遗传易感性女性在绝经后随着年龄的增长可能会越来越多地患上临床疾病。我们还假设，高酒精摄入量等因素可能会增加铁引起的疾病负担，血色素沉着症和阿尔茨海默病相关的载脂蛋白E变异可能对大脑造成特别大的损害。在这项建议中，我们寻求支持来描述铁相关基因变异对中老年健康的影响。我们计划使用来自英国生物库队列的世界领先数据，以及加拿大老龄化纵向研究和美国健康和退休研究。英国生物库将公布延长的临床随访(基线后不久为14年)、血液分析、成像和生存率的新数据。我们的目标是分析来自三个队列的数据，并澄清铁水平受遗传影响的变化对人类健康的影响，特别是在老年人。因此，该项目将具有成本效益地利用已经在英国生物库和其他基因分型队列中进行的大量投资。

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.