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 B Jenkins; Margaret Wrensch; Stephen S Francis

doi:10.1016/j.ajhg.2022.04.011

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

Am J Hum Genet. 2022 Jun 2;109(6):1105-1116. doi: 10.1016/j.ajhg.2022.04.011. Epub 2022 May 11.

Authors

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: geno.guerra@ucsf.edu.
² Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Pediatrics, University of California, San Francisco, Oakland, CA, USA.
⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA.
⁸ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA. Electronic address: stephen.francis@ucsf.edu.

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). GRS_ZEBRA and GRS_MCV were associated in opposite directions with risk of IDH wild-type gliomas (OR_ZEBRA = 0.91, p = 0.0099/OR_MCV = 1.11, p = 0.0054). GRS_EBNA 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-DQA1^∗03:01 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.

Keywords: Epstein-Barr virus; Merkel cell polyomavirus; glioma; human leukocyte antigen; polygenic risk score.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Viral
Epstein-Barr Virus Infections* / complications
Glioma* / complications
Glioma* / genetics
Herpesvirus 4, Human / genetics
Humans
Immunogenetics
Multiple Sclerosis* / genetics

Substances

Antigens, Viral

Abstract

Publication types

MeSH terms

Substances

Grants and funding