The Immunogenetics of Viral Antigen Response is Associated with Subtype-specific Glioma Risk and Survival

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2022 May 13

PMID 35550063

Authors

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 B Jenkins

Margaret Wrensch

Stephen S Francis

Affiliations

Soon will be listed here.

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) 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). GRS and GRS were associated in opposite directions with risk of IDH wild-type gliomas (OR = 0.91, p = 0.0099/OR = 1.11, p = 0.0054). GRS 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) 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.

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