Circulating vitamin D status and prognosis in colorectal cancer: a systematic review and meta-analysis with exploratory evidence on vitamin D receptor polymorphisms

Circulating 25-hydroxyvitamin D [25(OH)D] levels and genetic polymorphisms in the vitamin D receptor (VDR) have been explored as potential prognostic factors in colorectal cancer (CRC). This study aimed to investigate the association between circulating 25(OH)D levels and CRC prognostic outcomes, with a narrative evaluation of VDR polymorphisms. We performed a systematic literature search in the Cochrane Library, PubMed, ScienceDirect, and Scopus. The primary outcomes were CRC-specific survival, overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the random-effects model with inverse variance weighting, comparing high versus low 25(OH)D levels. Due to heterogeneity in genetic models and limited available data, VDR polymorphisms were synthesized using a narrative approach. Of the 61 studies included in the systematic review, 35 studies were included in the meta-analysis, which showed that higher 25(OH)D levels were associated with a lower risk of mortality, including a 26% lower CRC-specific mortality (HR 0.74; 95% CI 0.69–0.80; I2 = 0.01%), a 32% lower overall mortality (HR 0.68; 95% CI 0.64–0.72; I2 = 7.6%), and improved DFS (HR 0.71; 95% CI 0.61–0.83; I2 = 36.8%). The prognostic roles of VDR polymorphisms, particularly rs7975232 (ApaI), rs1544410 (BsmI), rs2228570 / rs10735810 (FokI), and rs731236 (TaqI) with CRC outcomes, including CRC-specific survival, OS, and DFS were reported across 18 studies. This study provides quantitative evidence supporting the potential prognostic relevance of circulating vitamin D levels in CRC. The role of VDR genetic polymorphisms remains inconclusive, warranting further investigations. The protocol of this systematic review and meta-analysis has been registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/), with the registration number CRD42024575841.