TY - JOUR
T1 - The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival
AU - Guerra, Geno
AU - Kachuri, Linda
AU - Wendt, George
AU - Hansen, Helen M.
AU - Mack, Steven J.
AU - Molinaro, Annette M.
AU - Rice, Terri
AU - Bracci, Paige
AU - Wiencke, John K.
AU - Kasahara, Nori
AU - Eckel-Passow, Jeanette E.
AU - Jenkins, Robert B.
AU - Wrensch, Margaret
AU - Francis, Stephen S.
N1 - Funding Information:
Work at University of California, San Francisco was supported by the National Institutes of Health (grant numbers T32CA151022 , K99CA246076 , R01CA52689 , P50CA097257 , R01CA126831 , R01CA139020 , R01AI128775 , and R25CA112355 ), the National Brain Tumor Foundation , the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research , the Robert Magnin Newman Endowed Chair in Neuro-oncology , and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, and William Martinusen. This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health , through UCSF-CTSI grant number UL1 RR024131 . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention ’s (CDC) National Program of Cancer Registries, under cooperative agreement 5NU58DP006344 ; the National Cancer Institute ’s Surveillance, Epidemiology, and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute, Cancer Registry of Greater California. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors.
Funding Information:
Work at University of California, San Francisco was supported by the National Institutes of Health (grant numbers T32CA151022, K99CA246076, R01CA52689, P50CA097257, R01CA126831, R01CA139020, R01AI128775, and R25CA112355), the National Brain Tumor Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, the Robert Magnin Newman Endowed Chair in Neuro-oncology, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, and William Martinusen. This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI grant number UL1 RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries, under cooperative agreement 5NU58DP006344; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute, Cancer Registry of Greater California. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors. G.G. L.K. and S.S.F. conceived of the study and wrote main drafts of the manuscript. G.G. L.K. G.W. S.J.M. N.K. and S.S.F. conducted and advised on informatic and statistical analyses along with result interpretations. H.M.H. A.M.M. T.R. P.B. J.K.W. J.E.E. R.B.J. and M.W. were involved in primary data collection. All authors contributed and reviewed the final manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2022
PY - 2022/6/2
Y1 - 2022/6/2
N2 - 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-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.
AB - 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-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.
KW - Epstein-Barr virus
KW - Merkel cell polyomavirus
KW - glioma
KW - human leukocyte antigen
KW - polygenic risk score
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U2 - 10.1016/j.ajhg.2022.04.011
DO - 10.1016/j.ajhg.2022.04.011
M3 - Article
C2 - 35550063
AN - SCOPUS:85131036483
SN - 0002-9297
VL - 109
SP - 1105
EP - 1116
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -