PMID- 35550063
OWN - NLM
STAT- MEDLINE
DCOM- 20220608
LR  - 20240214
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 109
IP  - 6
DP  - 2022 Jun 2
TI  - The immunogenetics of viral antigen response is associated with subtype-specific 
      glioma risk and survival.
PG  - 1105-1116
LID - S0002-9297(22)00159-8 [pii]
LID - 10.1016/j.ajhg.2022.04.011 [doi]
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 x 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 x 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.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Guerra, Geno
AU  - Guerra G
AD  - Department of Neurological Surgery, University of California, San Francisco, San 
      Francisco, CA, USA. Electronic address: geno.guerra@ucsf.edu.
FAU - Kachuri, Linda
AU  - Kachuri L
AD  - Department of Epidemiology and Biostatistics, University of California, San 
      Francisco, San Francisco, CA, USA.
FAU - Wendt, George
AU  - Wendt G
AD  - Department of Neurological Surgery, University of California, San Francisco, San 
      Francisco, CA, USA.
FAU - Hansen, Helen M
AU  - Hansen HM
AD  - Department of Neurological Surgery, University of California, San Francisco, San 
      Francisco, CA, USA.
FAU - Mack, Steven J
AU  - Mack SJ
AD  - Department of Pediatrics, University of California, San Francisco, Oakland, CA, 
      USA.
FAU - Molinaro, Annette M
AU  - Molinaro AM
AD  - 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.
FAU - Rice, Terri
AU  - Rice T
AD  - Department of Neurological Surgery, University of California, San Francisco, San 
      Francisco, CA, USA.
FAU - Bracci, Paige
AU  - Bracci P
AD  - Department of Epidemiology and Biostatistics, University of California, San 
      Francisco, San Francisco, CA, USA.
FAU - Wiencke, John K
AU  - Wiencke JK
AD  - 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.
FAU - Kasahara, Nori
AU  - Kasahara N
AD  - 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.
FAU - Eckel-Passow, Jeanette E
AU  - Eckel-Passow JE
AD  - Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
FAU - Jenkins, Robert B
AU  - Jenkins RB
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
FAU - Wrensch, Margaret
AU  - Wrensch M
AD  - 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.
FAU - Francis, Stephen S
AU  - Francis SS
AD  - 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.
LA  - eng
GR  - R01 CA139020/CA/NCI NIH HHS/United States
GR  - HHSN261201800009C/CA/NCI NIH HHS/United States
GR  - NU58DP006344/DP/NCCDPHP CDC HHS/United States
GR  - T32 CA151022/CA/NCI NIH HHS/United States
GR  - R01 CA230712/CA/NCI NIH HHS/United States
GR  - R25 CA112355/CA/NCI NIH HHS/United States
GR  - HHSN261201800015I/CA/NCI NIH HHS/United States
GR  - R01 CA126831/CA/NCI NIH HHS/United States
GR  - UL1 RR024131/RR/NCRR NIH HHS/United States
GR  - P50 CA097257/CA/NCI NIH HHS/United States
GR  - HHSN261201800032I/CA/NCI NIH HHS/United States
GR  - HHSN261201800015C/CA/NCI NIH HHS/United States
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - HHSN261201800032C/CA/NCI NIH HHS/United States
GR  - P30 CA015083/CA/NCI NIH HHS/United States
GR  - K99 CA246076/CA/NCI NIH HHS/United States
GR  - R01 CA052689/CA/NCI NIH HHS/United States
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
GR  - HHSN261201800009I/CA/NCI NIH HHS/United States
GR  - R01 AI128775/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220511
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (Antigens, Viral)
SB  - IM
MH  - Antigens, Viral
MH  - *Epstein-Barr Virus Infections/complications
MH  - *Glioma/complications/genetics
MH  - Herpesvirus 4, Human/genetics
MH  - Humans
MH  - Immunogenetics
MH  - *Multiple Sclerosis/genetics
PMC - PMC9247888
OTO - NOTNLM
OT  - Epstein-Barr virus
OT  - Merkel cell polyomavirus
OT  - glioma
OT  - human leukocyte antigen
OT  - polygenic risk score
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2022/05/14 06:00
MHDA- 2022/06/09 06:00
PMCR- 2022/12/02
CRDT- 2022/05/13 12:22
PHST- 2021/11/29 00:00 [received]
PHST- 2022/04/18 00:00 [accepted]
PHST- 2022/05/14 06:00 [pubmed]
PHST- 2022/06/09 06:00 [medline]
PHST- 2022/05/13 12:22 [entrez]
PHST- 2022/12/02 00:00 [pmc-release]
AID - S0002-9297(22)00159-8 [pii]
AID - 10.1016/j.ajhg.2022.04.011 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2022 Jun 2;109(6):1105-1116. doi: 10.1016/j.ajhg.2022.04.011. 
      Epub 2022 May 11.