Abstract 5220: Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts
Authors: Kim Hanseul , Yuan Chen , Nguyen Long H. , Ng Kimmie , Giovannucci Edward L. 
Published: April 2023

Abstract
Background: Lower levels of 25-hydroxyvitamin D [25(OH)D], a major form of circulating vitamin D, have consistently been associated with higher mortality among colorectal cancer (CRC) patients, though the dose-response relation is not well characterized {Ng 2008; Fedirko 2012; Wesa 2015; Zgaga 2014}. A study showed a strong effect modification (P for interaction = 0.0002) {Gibbs 2020} by Gc2 (or, vitamin D-binding protein) isoform where patients with the isoform had significantly higher mortality if they had deficient vitamin D levels. However, it is unknown whether this association differs by Gc isoforms in other populations.
Methods: We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among CRC patients within the two ongoing prospective US cohorts: Nurses’ Health Study and Health Professionals Follow-Up Study. Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). We evaluated potential nonlinear association using the restricted cubic splines and assessed effect modification by Gc2 isoform with stratified analyses. Individuals with the Gc rs4588 CC, CA and AA genotypes were classified as having Gc1-1, Gc1-2, and Gc2-2 isoforms, respectively. Participants with a minor allele at Gc rs4588 (rs4588*CA or rs4588*AA genotypes) were defined as having the Gc2 isoform.
Results: A total of 588 patients were observed until the date of death or last follow-up in 2018, whichever came first. Deficient versus sufficient 25(OH)D concentrations (&lt;30 vs ≥50 nmol/L) were associated with higher overall mortality (HR, 2.06; 95% CI, 1.34-3.18) and suggestively with higher CRC-specific mortality (HR, 1.51; 95% CI, 0.75-3.07). Spline results showed that the potential beneficial role of vitamin D plateaued around 50 nmol/L (P for nonlinearity = 0.04). The HRs for overall mortality comparing deficient versus sufficient concentrations were 2.43 (95% CI, 1.26-4.70) for patients with Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI, 0.88-3.02) for patients with Gc1-2 or Gc2-2 (rs4588 CA or AA) isoforms (P for interaction = 0.54). The HRs for CRC-specific mortality were 1.18 (95% CI, 0.27-5.14) for patients with Gc1-1 isoform and 1.41 (95% CI, 0.62-3.24) for patients with Gc1-2 or Gc2-2 isoforms (P for interaction = 0.94).
Conclusions: We found that lower 25(OH)D levels up to 50 nmol/L were associated with higher overall mortality, but this association did not differ by Gc isoforms in the two US cohorts.
Citation Format: Hanseul Kim, Chen Yuan, Long H. Nguyen, Kimmie Ng, Edward L. Giovannucci. Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5220.