The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival

Geno Guerra, Linda Kachuri, George Wendt, Helen M. Hansen, Steven J. Mack, Annette M. Molinaro, Terri Rice, Paige Bracci, John K. Wiencke, Nori Kasahara, Jeanette E. Eckel-Passow, Robert Brian Jenkins, Margaret Wrensch, Stephen S. Francis

Research output: Contribution to journalArticlepeer-review

Abstract

Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p < 5 × 10−8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution by using data from 3,418 glioma-affected individuals subtyped by somatic mutations and 8,156 controls. Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p < 0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild-type gliomas (ORZEBRA = 0.91, p = 0.0099/ORMCV = 1.11, p = 0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR = 1.09, p = 0.040) and improved survival (HR = 0.86, p = 0.010). HLA-DQA103:01 was significantly associated with decreased risk of glioma overall (OR = 0.85, p = 3.96 × 10−4) after multiple testing adjustment. This systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral-based therapies in glioma treatment.

Original languageEnglish (US)
Pages (from-to)1105-1116
Number of pages12
JournalAmerican journal of human genetics
Volume109
Issue number6
DOIs
StatePublished - Jun 2 2022

Keywords

  • Epstein-Barr virus
  • glioma
  • human leukocyte antigen
  • Merkel cell polyomavirus
  • polygenic risk score

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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