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[Preprint]. 2023 Oct 16:2023.10.15.23296448.
doi: 10.1101/2023.10.15.23296448.

Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Linda Kachuri  1   2 , Geno A Guerra  3   4 , George A Wendt  3 , Helen M Hansen  3 , Annette M Molinaro  3   4 , Paige Bracci  4 , Lucie McCoy  3 , Terri Rice  3 , John K Wiencke  3   5 , Jeanette E Eckel-Passow  6 , Robert B Jenkins  7 , Margaret Wrensch  3 , Stephen S Francis  3   4   5
Affiliations

Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Linda Kachuri et al. medRxiv. .

Update in

Abstract

Glioma is a highly fatal brain tumor comprised of molecular subtypes with distinct clinical trajectories. Observational studies have suggested that variability in immune response may play a role in glioma etiology. However, their findings have been inconsistent and susceptible to reverse causation due to treatment effects and the immunosuppressive nature of glioma. We applied genetic variants associated (p<5×10-8) with blood cell traits to a meta-analysis of 3418 glioma cases and 8156 controls. Genetically predicted increase in the platelet to lymphocyte ratio (PLR) was associated with an increased risk of glioma (odds ratio (OR)=1.25, p=0.005), especially in IDH-mutant (IDHmut OR=1.38, p=0.007) and IDHmut 1p/19q non-codeleted (IDHmut-noncodel OR=1.53, p=0.004) tumors. However, reduced glioma risk was observed for higher counts of lymphocytes (IDHmut-noncodel OR=0.70, p=0.004) and neutrophils (IDHmut OR=0.69, p=0.019; IDHmut-noncodel OR=0.60, p=0.009), which may reflect genetic predisposition to enhanced immune-surveillance. In contrast to susceptibility, there was no association with survival in IDHmut-noncodel; however, in IDHmut 1p/19q co-deleted tumors, we observed higher mortality with increasing genetically predicted counts of lymphocytes (hazard ratio (HR)=1.65, 95% CI: 1.24-2.20), neutrophils (HR=1.49, 1.13-1.97), and eosinophils (HR=1.59, 1.18-2.14). Polygenic scores for blood cell traits were also associated with tumor immune microenvironment features, with heterogeneity by IDH status observed for 17 signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. In summary, we identified novel, immune-mediated susceptibility mechanisms for glioma with potential disease management implications.

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Conflict of interest statement

DISCLOSURES The authors have no disclosures to report.

Figures

Figure 1:
Figure 1:. Mendelian randomization results for glioma overall.
Visualization of odds ratios (OR) and 95% confidence intervals (CI) for the effect of increasing blood cell counts or blood cell ratios on the risk of glioma overall. For each blood cell phenotype, association results are shown for five Mendelian randomization estimation methods.
Figure 2:
Figure 2:. Mendelian randomization results for IDH mutated (IDHmut) glioma.
Visualization of odds ratios (OR) and 95% confidence intervals (CI) for the effect of increasing blood cell counts or blood cell ratios on the risk of IDHmut glioma and further stratified by the presence of 1p/19q co-deletion. For each blood cell phenotype, association results are shown for five Mendelian randomization estimation methods.
Figure 3:
Figure 3:. Mendelian randomization results for IDH wildtype (IDHwt) glioma.
Visualization of Mendelian randomization odds ratios (OR) and 95% confidence intervals (CI) for the effect of increasing blood cell counts or blood cell ratios on the risk of IDHwt glioma overall. For each blood cell phenotype, association results are shown for five Mendelian randomization estimation methods.
Figure 4:
Figure 4:. Meta-analysis of blood cell trait polygenic scores (PGS) associations with survival.
Hazard ratios (HR) and 95% confidence intervals (CI) correspond to the effect of a standard deviation increase in the standardized PGS on all-cause mortality. P-values are reported for statistically significant associations. The sample size and corresponding number of mortality events is reported for each glioma subgroup.
Figure 5:
Figure 5:. Associations of blood cell trait polygenic scores (PGS) with tumor immune microenvironment (TIME) features in TCGA.
Associations for selected blood cell trait PGS with heritable tumor immune microenvironment features identified in TCGA by Sayaman et al. (2021). Heterogeneity in PGS effect on specific TIME features between IDH-mutated and IDH-wildtype tumors was tested using Cochran’s Q test. Beta coefficients for Enrichment Score (ES) phenotypes were estimated per 10-unit change.
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