Abstract
Background High circulating levels of vitamin D (25(OH)D) are suggested to reduce the risk of urinary bladder cancer (BC), but the evidence is weak, and several studies lack sufficient adjustment for potential confounders (e.g., smoking, body mass index (BMI), and physical activity). Moreover, few studies have investigated the role of vitamin D‐binding protein (DBP) in this context. We conducted a matched nested case–control study including 378 cases and 378 controls within the Norwegian population‐based Janus cohort, using serum collected 5–41 years prior to diagnosis, to study 25(OH)D and BC risk, by taking circulating DBP into account.MethodsCox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, an estimate of unbound (free) 25(OH)D levels. We adjusted for smoking (status and pack‐years), BMI, physical activity, education and (mutually) for 25(OH)D and DBP. Restricted cubic splines were employed to examine nonlinear associations.ResultsHigh optimal levels of circulating 25(OH)D (≥100 nmol/L) (HR 0.35, 95% CI 0.19–0.64) were associated with decreased BC risk, when compared with insufficient concentrations (50–74 nmol/L). This association was less pronounced for optimal levels (75–99 nmol/L) (HR = 0.69, 95% CI 0.47–1.01). Moreover, estimated free 25(OH)D, was associated with decreased BC risk for molar ratio 17–21 (HR 0.66, 95% CI 0.44–0.97) and ≥22 (HR 0.50, 95% CI 0.29–0.82), compared to molar ratio 11–16. The HR function for BC risk was not linear, rather reversed u‐shaped, with the highest HR at 62.5 nmol/L and 13.5 molar ratio, respectively.ConclusionHigh levels of total and estimated free 25(OH)D were associated with reduced risk of BC, compared with insufficient concentrations. DBP was not associated with BC risk. We did not observe any impact of DBP or any of the studied lifestyle factors on the association between 25(OH)D and BC.
Highlights
Urinary bladder cancer (BC) is the most common genitourinary malignancy after prostate cancer worldwide.[1]
| 4111 high optimal levels (≥100 nmol/L) were associated with subsequent decreased BC risk when compared with insufficient concentrations (50–7 4 nmol/L)
Free levels of 25(OH)D in circulation, the 25(OH)D:D-binding protein (DBP) molar ratio, was associated with decreased BC risk, when comparing high molar ratios (17–21 and ≥22) with the reference category. For both total and estimated free 25(OH)D, modeling the hazard ratios (HRs) for the effect on BC risk by splines revealed that the effect was not linear, rather reversed u-s haped, with the highest HR at 62.5 nmol/L and 13.5 molar ratio, respectively, and with a decrease thereafter
Summary
Urinary bladder cancer (BC) is the most common genitourinary malignancy after prostate cancer worldwide.[1]. In associations with cancer risk, it is unknown whether the total or the free state is more relevant to study. Several observational studies report associations between circulating 25(OH)D concentrations and cancer risk at various sites, including BC.[18] The most recent meta-analysis on circulating 25(OH)D levels and BC risk, found a reduced risk of BC with higher concentrations of 25(OH)D.19,20. The individual studies did not report a clear association, and they vary according to adjustment for factors such as smoking history, BMI, and physical activity, which are related to the levels of 25(OH)D.21,22. We used stored serum from the population- based Janus Serum Bank Cohort (Janus Cohort) to examine total and free 25(OH)D as well as circulating DBP in relation to subsequent BC risk. We examined potential interactions with smoking, BMI and physical activity
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