Vitamin D-binding protein and pancreatic cancer: a nested case-control study.

BACKGROUND: Vitamin D-binding protein (DBP) is the primary carrier of 25-hydroxyvitamin D [25(OH)D] in the circulation. One prospective study in male smokers found a protective association between DBP and pancreatic cancer, particularly among men with higher 25(OH)D concentrations. OBJECTIVE: The objective was to examine the association between DBP and pancreatic cancer risk in an American population. DESIGN: We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial cohort of men and women aged 55-74 y at baseline. Between 1993 and 2010, 295 incident pancreatic adenocarcinoma cases were reported (follow-up to 15.1 y). Two controls (n = 590) were matched to each case by age, race, sex, and month of blood draw. We calculated smoking- and diabetes-adjusted ORs and 95% CIs with the use of conditional logistic regression. RESULTS: DBP concentration was not significantly associated with pancreatic cancer overall [highest (≥7149.4 nmol/L) vs. lowest (<3670.4 nmol/L) quintile; OR: 1.75; 95% CI: 0.91, 3.37; P-trend = 0.25]. For serum 25(OH)D compared with the referent (50 to <75 nmol/L), individuals in the highest group had a significantly higher risk (≥100 nmol/L; OR: 3.23; 95% CI: 1.24, 8.44), whereas those in the lowest group had no significant association (<25 nmol/L; OR: 2.50; 95% CI: 0.92, 6.81). Further adjustment for DBP did not alter this association. CONCLUSION: Our results do not support the hypothesis that serum DBP or 25(OH)D plays a protective role in pancreatic cancer. This trial was registered at clinicaltrials.gov as NCT00339495.

Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti-cancer properties for vitamin D compounds. Prospective studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow-up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR = 0.60, 95% CI 0.38-0.94 for highest versus lowest quintile, p trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR = 0.82, 95% CI 0.54-1.26, and OR = 0.79, 95% CI 0.52-1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP.

Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer.

We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D-binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and statistical tests were two sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR = 1.81, 95% CI: 1.18-2.79 for highest vs. lowest quintile, p-trend = 0.001) compared to those with DBP below the median (OR = 1.22, 95% CI: 0.81-1.84, p-trend 0.97; p-interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR = 0.96, 95% CI: 0.70-1.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower (

Markers of microbial translocation and risk of AIDS-related lymphoma.

BACKGROUND: Depletion of gut-associated lymphocytes by HIV infection facilitates microbial translocation, which may contribute to non-Hodgkin lymphoma (NHL) risk via chronic immune activation and B-cell hyperstimulation. METHOD: We therefore examined associations of four microbial translocation markers with subsequent NHL risk in a case-control study nested within four prospective cohort studies of HIV-infected individuals. Prediagnostic blood specimens for 56 NHL cases and 190 controls matched for age, sex, race, specimen type, cohort, and CD4 T-cell count were tested for the endotoxin lipopolysaccharide (LPS), antiendotoxin core antibody (EndoCab), LPS-binding protein (LBP), and soluble CD14 (sCD14). RESULTS: Elevated levels of sCD14 were associated with significantly increased NHL risk [odds ratio (OR) 2.72 (95% confidence interval [95% CI] 1.29-5.76)]. In subgroup analyses, elevated LPS levels were also associated with significantly increased NHL risk [OR 3.24 (95% CI 1.10-9.53)]. EndoCab and LBP levels were not associated with NHL risk. CONCLUSION: The association of sCD14 and LPS with NHL risk supports an etiologic role for gut microbial translocation in lymphomagenesis among HIV-infected individuals. Additional studies with larger sample sizes are needed to confirm these observations.

Impact of circulating vitamin D binding protein levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk: a nested case-control study.

High concentrations of circulating 25-hydroxyvitamin D [25(OH)D] have been associated with elevated pancreatic cancer risk. As this is contrary to an expected inverse association between vitamin D status and cancer, we examined whether vitamin D binding protein (DBP), the primary carrier of vitamin D compounds in circulation, plays a role in this relationship. Prediagnostic serum DBP and 25(OH)D were studied in relation to risk of pancreatic cancer in a nested case-control study of 234 cases and 234 controls in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. ORs and 95% CIs were estimated using logistic regression, and statistical tests were two-sided. We found that DBP and 25(OH)D were correlated (r = 0.27, P < 0.0001), and DBP was inversely associated with pancreatic cancer risk (OR = 0.66, 95% CI = 0.39-1.12, for the highest vs. lowest quartile; P(trend) = 0.02). Importantly, this association seemed to have a threshold between quartiles 2 to 4 and quartile 1, and was primarily evident among men with concurrent high 25(OH)D concentrations (OR = 0.33, 95% CI = 0.16-0.70 for highest vs. lowest quartile; P(trend) = 0.002), with no association in men with lower serum 25(OH)D (OR = 1.28, 95% CI = 0.62-2.61 for highest vs. lowest quartile, P(trend) 0.63, P(interaction) = 0.01). Men with higher 25(OH)D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR = 5.01, 95% CI 2.33-10.78, for highest vs. lowest quartile; P(trend) < 0.0001), while risk was weakly inversely associated with serum 25(OH)D when DBP concentrations were higher (P(interaction) = 0.001). Taken together, our findings indicate that higher DBP concentrations may sequester more 25(OH)D and reduce free 25(OH)D bioavailability. Simultaneous examination of DBP and 25(OH)D may be important in determining the association of vitamin D with cancer risk.

Supplementation with alpha-tocopherol or beta-carotene reduces serum concentrations of vascular endothelial growth factor-D, but Not -A or -C, in male smokers.

Evidence from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study suggests that vitamin E and ß-carotene supplement use may influence the risk of several cancers. Vascular endothelial growth factors (VEGF) are proteins involved in angiogenesis, an important requirement for tumor growth and metastasis. Thus, vitamin E and ß-carotene may influence cancer risk through one or more VEGF. The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial in which participants were assigned to 1 of 4 supplementation groups based on a 2 × 2 factorial design: 1) α-tocopherol (vitamin E); 2) ß-carotene; 3) both; or 4) placebo. For the present study, 100 cancer-free participants with follow-up serum available were randomly selected from each intervention group. VEGF-A, -C, and -D concentrations were measured by ELISA in serum obtained at baseline and after at least 2 y of supplementation. Differences in change in VEGF levels from baseline to follow-up between intervention groups were assessed using the ANOVA test. Change in VEGF-A and VEGF-C concentrations between baseline and follow-up did not differ by intervention group (P = 0.45 and 0.29, respectively). The decrease in the serum VEGF-D concentration was greater in the men supplemented with α-tocopherol (-9.7 ± 2.5%) or ß-carotene (-8.5 ± 2.7%) and tended to be greater in those supplemented with both (-6.8 ± 2.4%) compared to the placebo group, in which there was no change (-0.4 ± 3.0%) (P = 0.03). In this population of male smokers, supplementation with α-tocopherol or ß-carotene was associated with a decrease in VEGF-D levels over time. Although the mechanism through which these supplements affect cancer etiolog remains unclear, our results support the hypothesis that vitamin E and ß-carotene may influence cancer progression through VEGF-mediated lymphangiogenesis.