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

Background Multiple studies have implicated infections in glioma susceptibility, but the 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 10 viral antigens to investigate the relationship and glioma risk and survival. Methods Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5x10-8) 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 using data from 3418 glioma patients and 8156 controls. Results Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were suggestively associated with glioma risk and survival (unadjusted p<0.05). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (Odds ratio ORZEBRA=0.91, p=0.007 / ORMCV=1.11, p=0.005). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.04) and improved survival (Hazard ratio HR=0.86, p=0.01). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96x10-4) after multiple testing adjustment. Conclusion This first 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 also inform applications of antiviral based therapies in the treatment of glioma.

Relationship between genetically determined telomere length and glioma risk

Background Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls). Methods We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data. Results Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10−4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10−5), 5p15.33 (TERT; PSMR = 9.80 × 10−27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10−5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10−4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10−2), 6p21.3 (PSMR = 9.76 × 10−3), 6p22.2 (PSMR = 5.45 × 10−3), 7q31.33 (PSMR = 6.52 × 10−3), and 11q22.3 (PSMR = 8.89 × 10−4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma. Conclusions These observations extend the role of telomere-related genes in the development of glioma.

A Prospective Study of Dietary Flavonoid Intake and Risk of Glioma in US Men and Women

Objectives Flavonoids are a diverse group of plant constituents with demonstrated neuroprotective and anti-tumor effects. Flavonoid intake may decrease glioma risk, an association that has not yet been investigated in humans. The objective of this study was to evaluate the association between dietary flavonoid consumption and glioma risk in participants in the female Nurses’ Health Study (1984–2014, n = 81,688) and Nurses’ Health Study II (1991–2017, n = 95,228), and the male Health Professionals Follow-up Study (1986–2014, n = 49,884). Methods Exposure was average long-term (up to 30 years) and recent (up to 12 years) intake of total flavonoids and six flavonoid subclasses, derived from validated quadrennial food frequency questionnaires. The primary outcome was incident glioma, confirmed by medical record review. Results We documented 536 incident cases of glioma across 5,936,386 person-years of follow-up. Long-term total flavonoid, flavan-3-ol, and polymer intake was associated with decreased glioma risk in pooled analyses comparing highest to lowest quintile of consumption (total flavonoid hazard ratio (HR) = 0.79, 95% CI: 0.59–1.05, P-trend = 0.04; flavan-3-ol HR = 0.76, 95% CI: 0.57–1.01, P-trend = 0.04; polymer HR = 0.82, 95% CI: 0.61–1.09, P-trend = 0.05). Associations with recent intake were weaker and not statistically significant. There were no associations with other flavonoid subclasses. After additional adjustment for tea consumption, there was no significant association between flavan-3-ol or polymer consumption and glioma. Conclusions Increased dietary intake of flavan-3-ol and polymeric flavonoids, especially those predominant in tea, was associated with decreased glioma risk in a prospective cohort of men and women. Habitual consumption of foods and beverages containing flavan-3-ols and polymeric flavonoids may protect against the development of glioma. Funding Sources This work was supported by the U.S. National Institutes of Health.

Pre-diagnostic circulating concentrations of fat-soluble vitamins and risk of glioma in three cohort studies

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts—UK Biobank (UKB), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68–1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51–1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56–2.38). Nonsignificant associations were observed for α-tocopherol (MVRRtertile3vs1 = 0.61, 95% CI 0.29–1.32) and γ-tocopherol (MVRR tertile3vs1 = 1.30, 95% CI 0.63–2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.

The Influence of NDRG1 Single Nucleotide Polymorphisms on Glioma Risk and Prognosis in Chinese Han Population

Background: glioma is a highly fatal malignant tumor with a high recurrence rate. We aimed to determine the association between single nucleotide polymorphisms (SNPs) of NDRG1 and glioma risk and prognosis in the Chinese Han population.Methods: 5 candidate SNPs were genotyped by Agena MassARRAY; logistic regression was used to analyze the association between SNPs and glioma risk; We used multi-factor dimensionality reduction to analyze the interaction of ‘SNP-SNP’; the prognosis analysis was performed by log-rank test, Kaplan–Meier analysis and Cox regression model.Results: our results showed that the rs3808599 was associated with the reduction of glioma risk in all participants (p = 0.024) and the participants ≤40 years old (p = 0.020). rs3802251 may reduce glioma risk in all participants (p = 0.008), the male (p = 0.033) or astrocytoma patients (p = 0.023). rs3779941 was associated with poor glioma prognosis in the all participants (p = 0.039) or astrocytoma patients (p = 0.038). We also found that the key factors for glioma prognosis may include surgical operation, radiotherapy and chemotherapy.Conclusion: this study is the first to find that NDRG1 gene polymorphisms may have a certain association with glioma risk or prognosis in the Chinese Han population.