Lina Zgaga1, Evropi Theodoratou1, Susan M Farrington1, Farhat V N Din1, Li Yin Ooi1, Dominik Glodzik1, Susan Johnston1, Albert Tenesa1, Harry Campbell1, Malcolm G Dunlop2. 1. Lina Zgaga, Susan M. Farrington, Farhat V.N. Din, Li Yin Ooi, Dominik Glodzik, Albert Tenesa, Harry Campbell, and Malcolm G. Dunlop, University of Edinburgh and Western General Hospital; Evropi Theodoratou and Harry Campbell, University of Edinburgh, Edinburgh; Albert Tenesa, University of Edinburgh, Roslin; Susan Johnston, Glasgow Royal Infirmary, Glasgow, United Kingdom; Lina Zgaga, Trinity College Dublin, Dublin, Ireland. 2. Lina Zgaga, Susan M. Farrington, Farhat V.N. Din, Li Yin Ooi, Dominik Glodzik, Albert Tenesa, Harry Campbell, and Malcolm G. Dunlop, University of Edinburgh and Western General Hospital; Evropi Theodoratou and Harry Campbell, University of Edinburgh, Edinburgh; Albert Tenesa, University of Edinburgh, Roslin; Susan Johnston, Glasgow Royal Infirmary, Glasgow, United Kingdom; Lina Zgaga, Trinity College Dublin, Dublin, Ireland. malcolm.dunlop@igmm.ed.ac.uk.
Abstract
PURPOSE: We investigated whether the plasma level of 25-hydroxyvitamin D (25-OHD) after a diagnosis of colorectal cancer (CRC) influences survival outcome. PATIENTS AND METHODS: We prospectively studied 1,598 patients with stage I to III CRC. We sought association between plasma 25-OHD and stage-specific survival and tested for interaction between 25-OHD level and variation at the vitamin D receptor (VDR) gene locus. Blood was sampled postoperatively, and plasma was assayed for 25-OHD by liquid chromatography-tandem mass spectrometry. VDR polymorphisms (rs1544410, rs10735810, rs7975232, rs11568820) were genotyped, and haplotypes were inferred by using BEAGLE software. We tested for association between survival and 25-OHD, VDR genotype/haplotype, and after applying a VDR genotype-25-OHD interaction term. We conducted Kaplan-Meier survival analysis and used Cox proportional hazards models to estimate adjusted hazard ratios (HRs). RESULTS: We found strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality). We detected gene-environment interactions between 25-OHD concentration and rs11568820 genotype for CRC-specific (P = .008) and all-cause (P = .022) mortality, number of protective alleles (P = .004 and P = .018, respectively), and GAGC haplotype at the VDR locus for all-cause mortality (P = .008). CONCLUSION: In patients with stage I to III CRC, postoperative plasma vitamin D is associated with clinically important differences in survival outcome, higher levels being associated with better outcome. We observed interactions between 25-OHD level and VDR genotype, suggesting a causal relationship between vitamin D and survival. The influence of vitamin D supplementation on CRC outcome will require further investigation.
PURPOSE: We investigated whether the plasma level of 25-hydroxyvitamin D (25-OHD) after a diagnosis of colorectal cancer (CRC) influences survival outcome. PATIENTS AND METHODS: We prospectively studied 1,598 patients with stage I to III CRC. We sought association between plasma 25-OHD and stage-specific survival and tested for interaction between 25-OHD level and variation at the vitamin D receptor (VDR) gene locus. Blood was sampled postoperatively, and plasma was assayed for 25-OHD by liquid chromatography-tandem mass spectrometry. VDR polymorphisms (rs1544410, rs10735810, rs7975232, rs11568820) were genotyped, and haplotypes were inferred by using BEAGLE software. We tested for association between survival and 25-OHD, VDR genotype/haplotype, and after applying a VDR genotype-25-OHD interaction term. We conducted Kaplan-Meier survival analysis and used Cox proportional hazards models to estimate adjusted hazard ratios (HRs). RESULTS: We found strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality). We detected gene-environment interactions between 25-OHD concentration and rs11568820 genotype for CRC-specific (P = .008) and all-cause (P = .022) mortality, number of protective alleles (P = .004 and P = .018, respectively), and GAGC haplotype at the VDR locus for all-cause mortality (P = .008). CONCLUSION: In patients with stage I to III CRC, postoperative plasma vitamin D is associated with clinically important differences in survival outcome, higher levels being associated with better outcome. We observed interactions between 25-OHD level and VDR genotype, suggesting a causal relationship between vitamin D and survival. The influence of vitamin D supplementation on CRC outcome will require further investigation.
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