{"doi":"10.1101/2023.10.15.23296448","title":"Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival","abstract":"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 (IDH mut OR=1.38, p=0.007) and IDH mut 1p/19q non-codeleted (IDH mut-noncodel OR=1.53, p=0.004) tumors. However, reduced glioma risk was observed for higher counts of lymphocytes (IDH mut-noncodel OR=0.70, p=0.004) and neutrophils (IDH mut OR=0.69, p=0.019; IDH mut-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 IDH mut-noncodel; however, in IDH mut 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. SIGNIFICANCE This study suggests that genetic determinants of peripheral blood cell counts influence subtype-specific glioma susceptibility and mortality, with potential effects on the tumor immune microenvironment. These findings may have disease management implications.","journal":"medRxiv","year":2023,"id":412636,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":817876,"name":"Geno Guerra","orcid":"0000-0001-9870-9998","position":1,"is_corresponding":false},{"id":268237,"name":"George A. Wendt","orcid":"0000-0003-3608-9601","position":2,"is_corresponding":false},{"id":471625,"name":"Helen M. Hansen","orcid":"0000-0001-5456-4985","position":3,"is_corresponding":false},{"id":238091,"name":"Annette M. Molinaro","orcid":"0000-0002-9854-7404","position":4,"is_corresponding":false},{"id":107662,"name":"Paige M. Bracci","orcid":"0000-0001-9338-9307","position":5,"is_corresponding":false},{"id":471626,"name":"Lucie McCoy","orcid":"0000-0002-2728-6083","position":6,"is_corresponding":false},{"id":472445,"name":"Terri Rice","orcid":null,"position":7,"is_corresponding":false},{"id":264802,"name":"John K. Wiencke","orcid":"0000-0001-7101-6489","position":8,"is_corresponding":false},{"id":414223,"name":"Jeanette E. Eckel‐Passow","orcid":"0000-0002-6113-1114","position":9,"is_corresponding":false},{"id":226434,"name":"Robert B. Jenkins","orcid":"0000-0002-4049-694X","position":10,"is_corresponding":false},{"id":264805,"name":"Margaret Wrensch","orcid":"0000-0002-3070-7600","position":11,"is_corresponding":false},{"id":268235,"name":"Stephen Francis","orcid":"0000-0002-6488-6272","position":12,"is_corresponding":false},{"id":233918,"name":"Linda Kachuri","orcid":"0000-0002-3226-4727","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:21:50.261851Z","pmid":"37905116","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}