Abstract
The varicella-zoster virus (VZV) infects >95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and individuals who are immunocompromised. However, HZ can occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in patients with HZ using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ human leukocyte antigen association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the major histocompatibility complex locus for HZ development, identifying 5 protective and 4 risk human leukocyte antigen alleles. This demonstrates that HZ susceptibility is largely governed by variations in the major histocompatibility complex. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.