The clinical impact of inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6): a comprehensive analysis using UK Biobank

遗传性染色体整合型人类疱疹病毒 6 (iciHHV-6) 的临床影响：使用英国生物银行的综合分析

• 批准号: MR/T030941/1
• 负责人: Ruth Jarrett
• 金额: $ 154.24万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT030941%2F1
• 关键词: clinical; impact; inherited; chromosomally; integrated

Most people are infected by human herpesvirus 6A or 6B (HHV-6A or HHV-6B) in early childhood, and the virus then persists in a small number of cells in the body for life. However, in some people the virus is acquired by a completely different route - it is inherited from their parents. In these individuals, the DNA content of the virus (the viral genome) is present in every cell in the body and is passed on to successive generations in germ cells, i.e. sperm or ova. This phenomenon is called inherited chromosomally-integrated HHV-6 or iciHHV-6 for short. Tens of millions of people worldwide have iciHHV-6, and we estimate that around 1.2% of the UK population (~750,000 individuals) is affected, but little is known of the consequences. iciHHV-6 arises because the virus can insert its genome into structures at the ends of chromosomes called telomeres. Telomeres protect the ends of chromosomes from damage and have been likened to plastic tips at the end of shoelaces. Telomeres get shorter as people age, and shorter telomeres are associated with the development of age-related diseases. Recent studies show that iciHHV-6 genomes are sometimes released from telomeres; this causes sudden shortening of the telomere and can lead to viral reactivation with the production of infectious virus. Case studies provide evidence that viral reactivation does occur in iciHHV-6-positive people, and that release of viral genomes may play a role in the development of cancer; however, the frequency of these events is not clear. Analysis of two large cohort studies has also revealed an unexpected association between iciHHV-6 and angina-like chest pains. Thus, iciHHV-6 is not simply a fossilised viral remnant but can cause disease.The aim of this study is to evaluate the clinical importance of iciHHV-6 by analysing samples and data from 500,000 individuals in the UK Biobank cohort. We need a study of this size to show conclusively whether, or not, iciHHV-6 has a significant effect on health. The wealth of information within UK Biobank including questionnaire data, physical measurements, linkage to electronic health records, genome-wide genetic data, and more, make this the ideal resource for investigating disease associations with iciHHV-6. We will screen DNA samples from all UK Biobank participants for iciHHV-6 and characterise the viral genomes. For most individuals, we will also determine which telomere harbours the virus, since some effects may be chromosome-specific.We will analyse disease associations in three ways. First, we will determine whether we can detect associations with diseases that have been linked previously to HHV-6, such as Alzheimer's disease. Secondly, we will perform a large exploratory analysis to look for novel associations. Lastly, we will perform a detailed analysis of iciHHV-6 and angina, a type of chest pain caused by lack of blood flow to the heart. We will use the wide-ranging cardiovascular data in UK Biobank to find out why iciHHV-6-positive individuals are more likely to suffer from angina, and whether this has serious consequences such as progression to heart attack or dropping dead.We will determine whether iciHHV-6 has strong associations with some diseases and whether it contributes a small increase in the risk of others. iciHHV-6 might even protect against some diseases. We will also establish whether harmful effects of iciHHV-6 are common or whether they occur only rarely. Whatever the results, the findings will provide a solid evidence base for doctors and nurses advising individuals who are iciHHV-6-positive. If we discover new associations, as anticipated, the results will potentially benefit the millions of individuals and families who have iciHHV-6 through improved diagnosis and treatment.At the end of the study, we will return the results to the UK Biobank, so that they are available to other researchers for future studies; thus, the investigation of iciHHV-6 will continue beyond this study.

大多数人在儿童早期感染人类疱疹病毒6A或6 B（HHV-6A或HHV-6 B），然后病毒在体内的少数细胞中终生存在。然而，在一些人中，病毒是通过完全不同的途径获得的-它是从父母那里遗传的。在这些个体中，病毒的DNA含量（病毒基因组）存在于体内的每个细胞中，并在生殖细胞（即精子或卵子）中传递给后代。这种现象被称为遗传性染色体整合HHV-6或简称icihHV-6。全世界有数千万人感染了iciHHV-6，我们估计大约有1.2%的英国人口（约75万人）受到影响，但对后果知之甚少。iciHHV-6的出现是因为病毒可以将其基因组插入染色体末端称为端粒的结构中。端粒保护染色体末端不受损害，被比作鞋带末端的塑料尖端。端粒随着年龄的增长而变短，而较短的端粒与年龄相关疾病的发展有关。最近的研究表明，iciHHV-6基因组有时会从端粒中释放出来;这会导致端粒突然缩短，并可能导致病毒重新激活，产生感染性病毒。病例研究提供的证据表明，病毒重新激活确实发生在iciHHV-6阳性人群中，病毒基因组的释放可能在癌症的发展中发挥作用;然而，这些事件的频率尚不清楚。对两项大型队列研究的分析也揭示了iciHHV-6与心绞痛样胸痛之间的意外关联。因此，iciHHV-6不仅仅是一种病毒残留物，而且可以引起疾病。本研究的目的是通过分析英国生物库队列中50万人的样本和数据来评估iciHHV-6的临床重要性。我们需要一项这样规模的研究来最终证明iciHHV-6是否对健康有显著影响。英国生物库中丰富的信息，包括问卷数据，身体测量，与电子健康记录的联系，全基因组遗传数据等，使其成为研究与icihHV-6疾病相关性的理想资源。我们将从英国生物库的所有参与者中筛选CiHHV-6的DNA样本，并对病毒基因组进行测序。对于大多数个体，我们还将确定哪个端粒携带病毒，因为有些影响可能是染色体特异性的。首先，我们将确定我们是否可以检测与以前与HHV-6相关的疾病的关联，例如阿尔茨海默病。其次，我们将进行一个大型的探索性分析，以寻找新的关联。最后，我们将对iciHHV-6和心绞痛进行详细分析，心绞痛是一种由于缺乏血液流向心脏而引起的胸痛。我们将使用英国生物库中广泛的心血管数据来找出为什么iciHHV-6阳性个体更容易患心绞痛，以及这是否会导致严重的后果，如心脏病发作或猝死。我们将确定iciHHV-6是否与某些疾病有很强的关联，以及它是否会导致其他疾病风险的小幅增加。iciHHV-6甚至可以预防某些疾病。我们还将确定iciHHV-6的有害影响是常见的还是很少发生。无论结果如何，这些发现都将为医生和护士提供坚实的证据基础，为iciHHV-6阳性的个人提供建议。如果我们发现了新的关联，正如预期的那样，通过改进诊断和治疗，结果可能会使数百万携带iciHHV-6的个人和家庭受益。在研究结束时，我们将把结果返回英国生物库，以便其他研究人员在未来的研究中使用;因此，对iciHHV-6的调查将在本研究之后继续进行。