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

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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.