Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation

Background To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. Methods We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. Results We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55–0.76, P = 1.03 × 10 −7 ) and OS (HR = 0.66,95%CI = 0.58–0.75, P = 8.15 × 10 −11 ) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80–1.19, P = 0.83) or OS (HR = 1.07,95%CI = 0.91–1.25, P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85–1.28, P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93–1.31, P = 0.25). Conclusion This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.