GENETIC VARIATION, IRON AND LATER LIFE HEALTH OUTCOMES

遗传变异、铁和晚年健康结果

• 批准号: MR/S009892/1
• 负责人: David Melzer
• 金额: $ 37.18万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS009892%2F1
• 关键词: GENETIC; VARIATION; IRON; LATER; LIFE

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.

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，包括痴呆和其他神经系统疾病，肝癌和其他癌症，关节炎和糖尿病，但铁是否真的会导致所有这些疾病仍不清楚。铁水平在人体内受到严格控制，但已发现几种常见的遗传变异可增加铁水平。这些为研究不同铁水平对人类疾病的影响提供了强有力的工具。由于已经存在纠正铁水平的有效治疗方法，因此澄清铁在疾病中的作用可能会导致更好的预防和护理患者。铁相关变异是铁超负荷疾病血色病的驱动因素：英国和爱尔兰是世界上导致遗传性血色病的主要突变发生率最高的国家。在英国，大约每150名欧洲血统的人中就有1人（0.6%）是最高风险HFE C282Y变体的纯合子。MRC支持的英国生物库（UKB）迄今为止研究的HFE C282Y纯合子人数最多。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中，我们发现近1.6%的髋关节置换患者是C282 Y纯合子，这表明相关的关节问题可能很严重。我们还首次发现，C282Y与随着年龄增长的肌肉损失有关。我们的初步分析显示，使用C282Y的痴呆症诊断增加了一倍，加上英国生物银行大脑扫描中的铁沉积证据。在排除HFE C282Y后，其他铁相关的遗传变异也与60奥尔兹的几种疾病有关。在英国生物库中，随着时间的推移，新疾病发作的数量正在迅速增加，因此我们现在需要在收集的新临床数据中跟踪这项工作，加上越来越多的成像数据，以确定C282Y和其他铁相关突变的真实影响。有既定的治疗方法来降低铁水平，包括献血，尽管血色病的一些临床特征如果开始得太晚就会对治疗产生抗药性。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（可能包括一些痴呆症）的精确预防、诊断和治疗提供了难得的机会。我们假设，铁相关变异的组合可能导致铁过载的疾病风险，特别是在老年男性和女性中。由于铁水平降低月经，我们假设，妇女与遗传易感性铁超载可能会越来越多地发展临床疾病，因为他们的年龄超过更年期。我们还假设，诸如高酒精摄入等因素可能会增加铁的疾病负担，并且血色病和阿尔茨海默病相关ApoE变体的组合可能对大脑特别有害。在这项提案中，我们寻求支持，以证明铁相关的遗传变异对中年和晚年健康的影响。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与退休研究。英国生物银行将发布来自延长临床随访（基线后不久长达14年），血液分析，成像和生存的新数据。我们的目标是分析来自三个队列的数据，并澄清遗传影响的铁水平变化对人类健康的影响，特别是在老年人。因此，该项目将是对英国生物库和其他基因分型队列的大量投资的具有成本效益的利用。

项目成果

Genetic associations for two biological age measures point to distinct aging phenotypes.

• DOI: 10.1111/acel.13376
• 发表时间: 2021-06
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Kuo CL;Pilling LC;Liu Z;Atkins JL;Levine ME
• 通讯作者: Levine ME

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.

• DOI: 10.1002/hep.32575
• 发表时间: 2022-12
• 期刊: Hepatology (Baltimore, Md.)

Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank.

• DOI: 10.1158/1055-9965.epi-22-0284
• 发表时间: 2022-09-02
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank

HFE 血色病变异与临床疾病的外显率：英国生物银行的多基因风险评分关联

• DOI: 10.1101/2022.03.08.22272084
• 发表时间: 2022
• 作者: Pilling L

Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants.

遗传性血色素沉着病与虚弱、肌肉减少症和慢性疼痛的关联：来自 200,975 名英国生物银行老年参与者的证据。

• DOI: 10.1093/gerona/gly270
• 发表时间: 2019
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Tamosauskaite J