DENVER – Individuals carrying human herpesvirus 6 in their genome have a threefold increased risk of developing basal cell carcinoma, according to new research that relied on UK Biobank data, presented here at the American Society of Human Genetics annual meeting on Wednesday.
Biobanks with genome sequencing data represent a treasure trove for studying the human virome and its influence on human health since viral genomes that are present in participants' blood samples are automatically sequenced along with their human DNA.
"It turns out that there is 10 times more virus within us than human cells," Ryan Dhindsa, an assistant professor of pathology and immunology at Baylor College of Medicine, said in a conference talk. "But excluding the relatively small number of viruses that cause obvious medical disease, viruses remain largely understudied, and their impact on human health is largely unknown."
About 5 percent of sequencing reads in whole-genome sequencing data from resources like the UK Biobank or the All of Us program don't align with the human reference genome and are usually discarded, he said, "but it turns out that you can actually mine those data for viral reads, and then you can identify individuals who are carrying viruses in that population."
Moreover, since biobanks also have electronic health records for their participants available, researchers can study whether people carrying a particular virus at a certain level are at higher risk of developing diseases like cancer.
In their study, Dhindsa and his colleagues focused on human herpesvirus 6 (HHV-6), an extremely common virus that infects almost all humans before the age of 5. It comes in two versions, A and B, with HHV-6B being most common in the US and in Europe. While some infected by HHV-6 remain asymptomatic, others develop a skin rash and fever. The virus can also retreat and lay dormant in T cells for many years and become reactivated later in life when the host's immune system weakens.
Furthermore, HHV-6 can stably integrate into the telomeres of the human genome, a phenomenon called inherited chromosomally integrated HHV-6 (ici-HHV-6). As such, it can become inherited through the germline to the next generation. "Although we know that this can occur, it's still unclear how often it occurs, why it happens, who it happens to, and what the actual impact of ici-HHV-6 is on human health," Dhindsa said.
For their analysis, he and his colleagues mined blood-based whole-genome sequencing data for 490,000 participants in the UK Biobank for reads that mapped back to the HHV-6A and HHV-6B reference genomes. From the number of reads they found in an individual, they could distinguish between those who are latent carriers of the virus and ici-HHV-6 individuals who have it integrated in their genome. The prevalence of ici-HHV-6 individuals turned out to be about 1.35 percent, which Dhindsa said is concordant with smaller prior studies. Interestingly, they could carry up to six copies of the virus, he added.
To find out whether ici-HHV-6 individuals were at higher risk of disease or other clinical symptoms than the rest of the UK Biobank population, his team conducted a phenome-wide association study (PheWAS), looking for associations with about 1,000 quantitative traits and 14,000 binary phenotypes contained in individuals' electronic health records.
Ici-HHV-6 was strongly correlated with basal cell carcinoma (BCC), the most common cancer in the US, increasing the risk for this cancer by about threefold. This is the second strongest genetic risk factor for BCC after another, well-established skin cancer locus, Dhindsa said, and while BCC has a low mortality and metastasis rate, "given the sheer number of people who develop basal cell carcinoma, it poses a significant health problem in the US."
To find out what genetic factors make an individual susceptible to HHV-6 integrating into their genome, his team also conducted an exome-wide association study (ExWAS) and found more than 1,200 significant variants in 15 loci. However, it is currently unclear whether these variants are functional, which further experiments will need to clarify. Other future work will focus on finding out the mechanism by which ici-HHV-6 may contribute to the development of basal cell carcinoma.
In an interview, Dhindsa said he would like to expand his studies to any type of virus that can be found in blood-based whole-genome sequencing datasets from biobanks, noting that a preprint of the work he presented will be posted in the near future.