metabolic dysfunction and diabetes, factors which appear to be related to higher CRC risk. Material and methods In order to explore this question, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between serum calcium levels and the risk of colorectal cancer (CRC) development. 975 first incident CRC cases were matched to 975 matched controls from within the cohort by sex, age, study centre, length of follow-up and some additional relevant variables. Serum calcium levels were measured using reflection X-ray fluorescence spectrometry on the pre-diagnostically-collected serum samples from cases and matched controls.Conditional logistic regression was used to calculate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CIs). Results and discussions Higher levels of serum calcium were associated with reduced risk of CRC (OR Q5vs.Q1 =0.69, 95% CI: 0.48-0.99; p trend =0.02). Sub-group analyses by anatomical sub-site suggest that the observed inverse cancer risk association is apparent in the colon (OR Q5vs.Q1 =0.61, 95% CI: 0.38-0.98; p trend =0.04) and not in the rectum (OR Q5vs.Q1 =0.99, 95% CI: 0.53-1.85; p trend =0.54) where the association appeared to be non-linear. The magnitude of the association in the colon is similar to that observed with dietary calcium at the same anatomical site. Stratified analysis by sex is suggestive of a stronger association for men than women. Conclusion In conclusion, elevated serum calcium levels are inversely associated with risk of CRC development, with some evidence for heterogeneity by anatomical sub-site and sex. Additional studies are necessary to confirm these findings and to further investigate potential underlying mechanisms for the role of serum calcium in CRC development.
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