Association of circulating Vitamin D with colorectal cancer depends on Vitamin D-binding protein isoforms: A pooled, nested, case-control study

• Type of Material: Article
• Authors: David Corley Gibbs, Emory University; Mingyang Song, Harvard University; Marjorie McCullough, Emory University; Caroline Y. Um, American Cancer Society; Roberd Bostick, Emory University; Kana Wu, Harvard University; William Flanders, Emory University; Edward Giovannucci, Harvard University; Mazda Jenab, The Arctic University of Norway; Magritt Brustad, The Arctic University of Norway; Anne Tjønneland, Emory University; Aurora Perez-Cornago, University of Oxford; Antonia Trichopoulou, Kræftens Bekæmpelse; Konstantinos K. Tsilidis, Imperial College London; Johan Hultdin, Umeå Universitet; Aurelio Barricarte Gurrea, Navarra Public Health Institute; Bas Bueno-De-Mesquita, Imperial College London; Yahya Mahamat-Saleh, Centre de recherche en épidémiologie et santé des populations; Tilman Kühn, German Cancer Research Center; Marc J. Gunter, International Agency for Research on Cancer; Elisabete Weiderpass, International Agency for Research on Cancer; Veronika Fedirko, Emory University
• Language: English
• Date: 2020-02-01
• Publisher: Oxford University Press
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020. Published by Oxford University Press.
• Final Published Version (URL): http://dx.doi.org/10.1093/jncics/pkz083
• Title of Journal or Parent Work: JNCI Cancer Spectrum
• Volume: 4
• Issue: 1
• Start Page: pkz083
• End Page: pkz083
• Grant/Funding Information: AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236); The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ), and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer, National Research Council;; The American Cancer Society funds the creation, maintenance and updating of the Cancer Prevention Study-II cohort.; This study was partly supported by funding from World Cancer Research Fund (MCRF) International Grant Programme [WCRF 2011–443; principal investigator: M. Jenab].; ISCIII RETIC (RD06/0020) and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 for EPIC-Norfolk and C570/A16491 for EPIC-Oxford) and the Medical Research Council (1000143 for EPIC-Norfolk and MR/M012190/1 for EPIC-Oxford) (UK).; This research was supported by the National Cancer Institute of the National Institutes of Health under Award Number F30CA236231 (to DCG) and the Anne and Wilson P. Franklin Foundation (to RMB).
• Keywords: Protein isoforms; Vitamin D; Colorectal cancer; Control study

Abstract

Background: Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588∗A (Thr436Lys) variant encoding the Vitamin D-binding protein-2 (DBP2) isoform, which may affect Vitamin D status and bioavailability. Methods: We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided. Results: The odds of having 25(OH)D concentrations less than 50nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588∗A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, Ptrend = 1.2 x 10T8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (>50nmol/L), relative to deficient (<30nmol/L), were associated with a 53% lower CRC risk among individuals with the DBP2 isoform (RR = 0.47, 95% CI = 0.33 to 0.67), but with a non-statistically significant 12% lower risk among individuals without it (RR = 0.88, 95% CI = 0.61 to 1.27) (Pheterogeneity.01). Conclusions: Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to Vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention.