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

David C. Gibbs , Mingyang Song , Marjorie L. Mccullough , Caroline Y. Um , Roberd M. Bostick , Kana Wu , William Dana Flanders , Edward Luciano Giovannucci , Mazda Jenab (1) , Magritt Brustad , Anne Tjønneland , Aurora Perez-Cornago , Antonia D. Trichopoulou , Konstantinos K. Tsilidis , J. Hultdin , Aurelio Barricarte Gurrea , Bas H. Bueno-De-Mesquita , Yahya Mahamat-Saleh (2, 3, 4) , Tilman Kühn , Marc J.R. Gunter (1) , Elisabete Weiderpass (1) , Veronika Fedirko

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 CESP - Centre de recherche en épidémiologie et santé des populations
3 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
4 IGR - Institut Gustave Roussy

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.

Domaines: Sciences du Vivant [q-bio]

David C. Gibbs, Mingyang Song, Marjorie L. Mccullough, Caroline Y. Um, Roberd M. Bostick, et al.. Association of circulating Vitamin D with colorectal cancer depends on Vitamin D-binding protein isoforms: A pooled, nested, case-control study. JNCI Cancer Spectrum, 2020, 4 (1), ⟨10.1093/jncics/pkz083⟩. ⟨hal-03228162⟩