Inherited chromosomally integrated human herpesvirus 6: regional variation in prevalence, association with angina, and identification of ancestral viral lineages in two large UK studies

Abstract

Tens of millions of people worldwide have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), yet we know little about the consequences. iciHHV-6-positive individuals inherit the genome of HHV-6A or HHV-6B in the germline, and viral genomes are therefore present in every nucleated cell. To investigate the epidemiology of iciHHV-6 in the UK, almost 32,000 individuals were screened from two volunteer research studies: the family-based Generation Scotland: Scottish Family Health Study (GS:SFHS) and the Breakthrough Generations Study (BGS). iciHHV-6 prevalence in GS:SFHS was, to our knowledge, higher than that in other large studies at 2.74% (647/23,637), with an iciHHV-6B prevalence of 2.55%. Scottish participants were more likely to be iciHHV-6B-positive than English ( P < 0.001), and the BGS results suggested a north-south gradient of iciHHV-6B prevalence in mainland Britain. Disease association analysis confirmed the previously reported association with angina, with an odds ratio of 1.91 (95% confidence interval, 1.29, 2.82) following adjustment for known risk factors, providing compelling evidence that iciHHV-6 contributes to the risk of a common symptom. De novo integrations were not detected within GS:SFHS pedigrees; rather, our findings indicated that three viral lineages accounted for over 95% of iciHHV-6A-positive samples, and six viral lineages accounted for 90% of iciHHV-6B-positive samples in GS:SFHS. This study demonstrates that iciHHV-6 is common in the UK, shows significant regional heterogeneity in prevalence, is not entirely harmless, and is largely derived from a relatively small number of ancestral viral lineages.IMPORTANCEHuman herpesvirus 6 (HHV-6) has the unusual ability to integrate into the host chromosome telomeres. Most of the world's population is infected by HHV-6 in early childhood, but around 1% inherit the virus as a chromosomally integrated viral genome-referred to as inherited chromosomally integrated HHV-6 (iciHHV-6). Little is known about the consequences of iciHHV-6, which has the potential to cause disease through various mechanisms. Here, we have used large cohorts to study iciHHV-6 prevalence, lineages, and phenotypic associations. We replicate a previously reported association between iciHHV-6 and angina, suggesting that iciHHV-6 is not entirely benign. We show significant variation in iciHHV-6 prevalence within the UK with almost 3% of Scottish people carrying iciHHV-6. In the first detailed analysis of viral lineages at the population level, we show that 90% of iciHHV-6 is explained by nine ancestral viral lineages. These results have important implications for future disease association analyses.