Dataset Information

Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study.

ABSTRACT: Background:Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability. Methods:We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided. Results:The odds of having 25(OH)D concentrations less than 50?nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588*A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, P trend = 1.2 × 10-8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (??50?nmol/L), relative to deficient (

SUBMITTER: Gibbs DC

PROVIDER: S-EPMC7050153 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study.

Gibbs David Corley DC Song Mingyang M McCullough Marjorie L ML Um Caroline Y CY Bostick Roberd M RM Wu Kana K Flanders W Dana WD Giovannucci Edward E Jenab Mazda M Brustad Magritt M Tjønneland Anne A Perez-Cornago Aurora A Trichopoulou Antonia A Tsilidis Konstantinos K KK Hultdin Johan J Barricarte Gurrea Aurelio A Bueno-de-Mesquita Bas B Mahamat-Saleh Yahya Y Kühn Tilman T Gunter Marc J MJ Weiderpass Elisabete E Fedirko Veronika V

JNCI cancer spectrum 20191015 1

<h4>Background</h4>Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional <i>GC-</i>rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability.<h4>Methods</h4>We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matche ...[more]

PMID: 32337495

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Project description:ObjectiveTo examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations.DesignNested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries.Participants1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controlsMain outcome measuresCirculating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders.Results25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation.ConclusionsThe results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

Project description:Pooling biomarker data across multiple studies allows for examination of a wider exposure range than generally possible in individual studies, evaluation of population subgroups and disease subtypes with more statistical power, and more precise estimation of biomarker-disease associations. However, circulating biomarker measurements often require calibration to a single reference assay prior to pooling due to assay and laboratory variability across studies. We propose several methods for calibrating and combining biomarker data from nested case-control studies when reference assay data are obtained from a subset of controls in each contributing study. Specifically, we describe a two-stage calibration method and two aggregated calibration methods, named the internalized and full calibration methods, to evaluate the main effect of the biomarker exposure on disease risk and whether that association is modified by a potential covariate. The internalized method uses the reference laboratory measurement in the analysis when available and otherwise uses the estimated value derived from calibration models. The full calibration method uses calibrated biomarker measurements for all subjects, including those with reference laboratory measurements. Under the two-stage method, investigators complete study-specific analyses in the first stage followed by meta-analysis in the second stage. Our results demonstrate that the full calibration method is the preferred aggregated approach to minimize bias in point estimates. We also observe that the two-stage and full calibration methods provide similar effect and variance estimates but that their variance estimates are slightly larger than those from the internalized approach. As an illustrative example, we apply the three methods in a pooling project of nested case-control studies to evaluate (i) the association between circulating vitamin D levels and risk of stroke and (ii) how body mass index modifies the association between circulating vitamin D levels and risk of cardiovascular disease.

Project description:BackgroundHigh 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.

Dataset Information

Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study.

Publications

Association of Circulating Vitamin D With Colorectal Cancer Depends on Vitamin D-Binding Protein Isoforms: A Pooled, Nested, Case-Control Study.

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