Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study

David Corley Gibbs, Mingyang Song, Marjorie L McCullough, Caroline Y Um, Roberd M Bostick, Kana Wu, W Dana Flanders, Edward Giovannucci, Mazda Jenab, Magritt Brustad, Anne Tjønneland, Aurora Perez-Cornago, Antonia Trichopoulou, Konstantinos K Tsilidis, Johan Hultdin, Aurelio Barricarte Gurrea, Bas Bueno-de-Mesquita, Yahya Mahamat-Saleh, Tilman Kühn, Marc J GunterElisabete Weiderpass, Veronika Fedirko

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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 50 nmol/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 × 10-8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (≥ 50 nmol/L), relative to deficient (< 30 nmol/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.

Original languageEnglish
Pages (from-to)pkz083
JournalJNCI Cancer Spectrum
Volume4
Issue number1
DOIs
Publication statusPublished - Feb 2020
Externally publishedYes

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press.

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