{"doi":"10.1371/journal.pone.0315252","title":"Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial","abstract":"Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC-cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2). For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g., the OR for high vs. low vitamin D quintile was 1.09 (0.89-1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0.83-1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1.18, and 1.19 vs. 1.22 (all p-interaction ≥0.36). However, GC qualitatively modified the vitamin D-bladder cancer risk association: OR = 1.70 (95% CI 0.96-2.98) among those with the Gc1-1 isoform and 0.52 (0.28-0.96) among those with any Gc2 isoforms (p-interaction = 0.03). When modeled without regard for 25(OH)D, Gc isoforms were generally not associated with cancer risk, although melanoma risk was significantly lower among individuals with the \"f\" subtype of the Gc1-1 isoform, specifically HR = 0.83 (95% CI 0.70-0.98) for Gc1f-1s and 0.67 (0.45-1.00) for Gc1f-1f, compared to individuals with the Gc1s-Gc1s isoform. Vitamin D binding protein genetic isoforms may be associated with melanoma risk but do not modify the association between vitamin D status and cancer, with the possible exception of bladder cancer.","journal":"PLoS ONE","year":2024,"id":472790,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":777839,"name":"Dominick Parisi","orcid":null,"position":1,"is_corresponding":false},{"id":422749,"name":"Alison M. Mondul","orcid":"0000-0002-8843-1416","position":2,"is_corresponding":false},{"id":827667,"name":"Tracy M. Layne","orcid":"0000-0002-3733-4886","position":3,"is_corresponding":false},{"id":240804,"name":"Jiaqi Huang","orcid":"0000-0002-7808-9477","position":4,"is_corresponding":false},{"id":302477,"name":"Rachael Z. Stolzenberg‐Solomon","orcid":"0000-0003-3698-7006","position":5,"is_corresponding":false},{"id":302464,"name":"Regina G. Ziegler","orcid":"0000-0002-5100-9852","position":6,"is_corresponding":false},{"id":241831,"name":"Mark P. Purdue","orcid":"0000-0003-1177-3108","position":7,"is_corresponding":false},{"id":241825,"name":"Wen‐Yi Huang","orcid":"0000-0002-4440-3368","position":8,"is_corresponding":false},{"id":217938,"name":"Christian C. Abnet","orcid":"0000-0002-3008-7843","position":9,"is_corresponding":false},{"id":241828,"name":"Neal D. Freedman","orcid":"0000-0003-0074-1098","position":10,"is_corresponding":false},{"id":260582,"name":"Kai Yu","orcid":"0000-0002-5337-137X","position":11,"is_corresponding":false},{"id":218606,"name":"Demetrius Albanes","orcid":"0000-0001-8330-4293","position":12,"is_corresponding":false},{"id":240083,"name":"Stephanie J. Weinstein","orcid":"0000-0002-3834-1535","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:05:57.032095Z","pmid":"39705237","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":[]}