Serum 25-Hydroxyvitamin D Status and Vitamin D Supplements Use Are Not Associated with Low Back Pain in the Large UK Biobank Cohort.

Longitudinal studies assessing the association of vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels < 30 nmol/L, and vitamin D supplement (VDS) use with low back pain (LBP) are sparse. This investigation assessed the cross-sectional and longitudinal association of vitamin D status and VDS use with LBP among 135,934 participants from the UK Biobank cohort. Approximately 21.6% of the participants had vitamin D deficiency, while only 4% regularly took VDS. In the month before study enrollment, 3.8% of the population reported experiencing LBP. An additional 3.3% of the population were diagnosed with LBP by their general practitioners for the first time during a median follow-up of 8.5 years. Vitamin D deficiency and VDS use were cross-sectionally associated with LBP in age- and sex-adjusted models, but these associations were not evident in comprehensively adjusted models. In longitudinal analyses, both vitamin D deficiency and VDS use were not associated with LBP in any model after correction for multiple testing. In conclusion, not unexpectedly due to the fact that LBP is multifactorial, our findings provide no evidence for the role of the vitamin D status in the etiology of LBP.

Strong associations of serum selenoprotein P with all-cause mortality and mortality due to cancer, cardiovascular, respiratory and gastrointestinal diseases in older German adults.

BACKGROUND: Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects. METHODS: To assess the association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50-74 years at baseline. RESULTS: During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile's cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio [95% confidence interval]: 1.35 [1.21-1.50]). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 [1.04-1.49]), cancer mortality (1.31 [1.09-1.58]), respiratory disease mortality (2.06 [1.28-3.32]) and gastrointestinal disease mortality (2.04 [1.25-3.32]). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex; p = 0.008). CONCLUSIONS: In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed. TRIAL REGISTRATION: Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028).

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

Associations of 25-hydroxyvitamin D status and vitamin D supplementation use with mortality due to 18 frequent cancer types in the UK Biobank cohort.

BACKGROUND: Although the associations of serum 25-hydroxyvitamin D (25(OH)D) levels and vitamin D supplementation with total cancer mortality are well-known, evidence regarding the association of 25(OH)D and cancer site-specific mortality is predominantly limited to common cancer types, and most studies on vitamin D supplementation use have limitations on sample size and the adjustment of important confounding factors. METHODS: We used cause-specific Cox regression models adjusted for 48 covariates to assess the associations of vitamin D deficiency, insufficiency, and vitamin D supplementation use with mortality from any cancer and 18 specific cancers in 411,436 United Kingdom Biobank participants, aged 40-69 years. RESULTS: The majority of the study population had either vitamin D deficiency (21.1%) or insufficiency (34.4%). Furthermore, 4.1% and 20.3% of the participants regularly took vitamin D or multivitamin supplements, respectively. During a median follow-up of 12.7 years, vitamin D deficiency was associated with significantly increased mortality from total cancer and four specific cancers: stomach (hazard ratio, 95% confidence interval: 1.42, 1.05-1.92), colorectal (1.27, 1.07-1.50), lung (1.24, 1.10-1.40), and prostate (1.36, 1.06-1.75). Vitamin D insufficiency was associated with increased colorectal (1.14, 1.00-1.30) and lung cancer mortality (1.19, 1.08-1.32). Compared to non-users, vitamin D use was associated with lower lung cancer (0.75, 0.60-0.95) and total cancer mortality. Multivitamin use was associated with lower mortality from melanoma (0.64, 0.43-0.97). CONCLUSION: Vitamin D deficiency and insufficiency were associated with increased mortality from multiple common cancers. The potential to reduce cancer mortality by vitamin D supplementation in populations with low 25(OH)D levels should be further explored.

Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

Vitamin D Status, Cdx2 Genotype, and Colorectal Cancer Survival: Population-Based Patient Cohort.

According to recent evidence, the prognostic value of Vitamin D (VitD) status for colorectal cancer (CRC) patients might be confined to patients with the GG genotype of Cdx2, a functional polymorphism of the VitD receptor gene. We aimed to validate these findings in a cohort of CRC patients. Post-operative serum 25-hydroxyvitamin D concentration was determined by mass spectrometry and Cdx2 genotyping was performed from blood or buccal swabs using standard methods. Joint associations of VitD status and Cdx2 with overall survival (OS), CRC-specific survival (CSS), recurrence-free survival (RFS), and disease-free survival (DFS) were assessed using Cox regression. For patients with GG genotype, adjusted hazard ratios (95% confidence interval) for the associations of sufficient compared with deficient VitD were 0.63 (0.50-0.78), 0.68 (0.50-0.90), 0.66 (0.51-0.86), and 0.62 (0.50-0.77) for OS, CSS, RFS, and DFS, respectively. These associations were weaker and not statistically significant for the AA/AG genotype. Interaction between VitD status and genotype did not reach statistical significance. VitD deficiency is an independent predictor of poorer survival, particularly for the GG Cdx2 carriers, suggesting a potential role of VitD supplementation according to VitD status and genotype, which should be evaluated in randomised trials.

Effects of vitamin D supplementation on inflammatory response in patients with cancer and precancerous lesions: Systematic review and meta-analysis of randomized trials.

BACKGROUND & AIMS: Inflammation plays a key role in tumor development and progression. Vitamin D has potential tumor suppressing effects through modulation of inflammatory processes. The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to summarize and evaluate the effects of vitamin D3 supplementation (VID3S) on serum inflammatory biomarkers among patients with cancer or pre-cancerous lesions. METHODS: We searched PubMed, Web of Science and Cochrane databases until November 2022. The effects of VID3S were estimated from pooled standardized mean differences (SMDs) with their 95% confidence intervals (CIs) for inflammatory biomarker follow-up levels between intervention and control groups. RESULTS: Meta-analysis of eight RCTs (total of 592 patients with cancer or pre-cancerous conditions) showed that VID3S significantly lowered levels of serum tumor necrosis factor (TNF)-α (SMD [95%CI]: -1.65 [-3.07; -0.24]). VID3S also resulted in statistically non-significantly lower serum levels of interleukin (IL)-6 (SMD [95%CI]: -0.83, [-1.78; 0.13]) and C-reactive protein (CRP) (SMD [95%CI]: -0.09, [-0.35; 0.16]), whereas IL-10 levels were unaltered (SMD [95%CI]: -0.00, [-0.50; 0.49]). CONCLUSION: Our study shows evidence of a significant reduction of TNF-α levels by VID3S for patients with cancer or precancerous lesions. Patients with cancer or precancerous lesions may benefit from personalized VID3S in suppressing tumour-promoting inflammatory response. PROSPERO REGISTRATION NUMBER: CRD42022295694.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer.

BACKGROUND: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized. OBJECTIVE: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype. RESULTS AND LIMITATIONS: High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p > 0.05). Limitations include the nominal statistical significance and residual confounding. CONCLUSIONS: Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (*1F/*1F) genotype, a finding that will require further replication. PATIENT SUMMARY: It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why.

Real-world evidence for the effectiveness of vitamin D supplementation in reduction of total and cause-specific mortality.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have demonstrated the efficacy of vitamin D supplementation for reduced cancer mortality, all-cause mortality, and respiratory tract infections. However, whether and to what extent this translates into effectiveness in real-world practice is unknown. METHODS: We assessed the association of vitamin D supplement use (as an over-the-counter drug or as part of a multivitamin product), vitamin D deficiency (25-hydroxyvitamin D, 25[OH]D <30 nmol/L), and insufficiency (25[OH]D 30 to <50 nmol/L) with all-cause and cause-specific mortality in 445,601 participants, aged 40-73 years, from the UK Biobank cohort. RESULTS: A total of 4.3% and a further 20.4% of the study participants reported regularly taking vitamin D or multivitamin supplements, respectively. Still, the majority had either vitamin D deficiency (21.0%) or insufficiency (34.3%). We detected 49 independent determinants of vitamin D deficiency and vitamin D supplement use and used them to adjust Cox regression models for all mortality outcomes. A total of 29,107 (6.5%) participants died during a median follow-up time of 11.8 years. Both vitamin D deficiency and insufficiency were strongly associated with all mortality outcomes. Self-reported vitamin D supplement use (83% over-the-counter/17% prescription drugs) and multivitamin intake were significantly associated with 10% and 5% lower all-cause mortality, respectively. Furthermore, regular vitamin D supplement users had 11%, 11%, and 29% lower cancer, cardiovascular disease, and respiratory disease mortality than nonusers, respectively (not significant for cardiovascular disease mortality). CONCLUSION: This large study suggests that in the real world, the efficacy of vitamin D supplements in reducing mortality may be at least as good as observed in RCTs.

Efficacy and Safety of a Personalized Vitamin D3 Loading Dose Followed by Daily 2000 IU in Colorectal Cancer Patients with Vitamin D Insufficiency: Interim Analysis of a Randomized Controlled Trial.

A personalized vitamin D3 loading dose has not yet been tested in cancer patients. This interim analysis of the randomized, placebo-controlled VICTORIA trial analyzed the first recruited 74 German adults with nonmetastatic colorectal cancer, a tumor surgery within the past year, and 25-hydroxyvitamin D levels (25(OH)D) < 50 nmol/L. Study participants received a loading dose tailored for a baseline 25(OH)D level and BMI in the first 11 days, followed by a maintenance dose of 2000 IU of vitamin D3 daily until end of trial week 12. The mean 25(OH)D levels were 27.6, 31.0, and 34.1 nmol/L in the placebo group and 25.9, 63.1, and 75.5 nmol/L in the verum group during screening, visit 1 (end of loading dose), and visit 2 (end of maintenance dose), respectively. The prevalence of 25(OH)D) ≥ 50 nmol/L at visits 1 and 2 was 3.5% and 17.4% in the placebo group and 80.0% and 100% in the verum group. No events of 25(OH)D > 150 nmol/L or hypercalcemia were observed. Hypercalciuria events at visit 1 (n = 5 in verum and n = 1 in the placebo group; p = 0.209) receded after discontinuation of the study medication. The personalized loading dose effectively and safely increased the 25(OH)D levels, and 2000 IU of vitamin D3 daily sustained the achieved levels.

Consistent Inverse Associations of Total, "Bioavailable", Free, and "Non-Bioavailable" Vitamin D with Incidence of Diabetes among Older Adults with Lower Baseline HbA1c (≤6%) Levels.

BACKGROUND: Serum 25-hydroxyvitamin (25(OH)D) levels are inversely associated with risk of diabetes. The "free hormone hypothesis" suggests potential effects to be mainly related to concentrations of "bioavailable" and free rather than total 25(OH)D. We assessed associations of serum concentrations of vitamin D-binding protein (VDBP), as well as total "bioavailable", complementary "non-bioavailable", and free 25(OH)D, with the risk of developing diabetes among non-diabetic older adults in a large population-based cohort study in Germany. METHODS: We included 4841 non-diabetic older adults aged 50-75 years at the baseline exam from the ESTHER cohort conducted in Saarland, Germany, in 2001-2002. Concentrations of "bioavailable" and free 25(OH)D were derived from serum concentrations of VDBP, total 25(OH)D, and albumin. Incidence of diabetes was ascertained during up to 14 years of follow-up. Associations were quantified by multivariable Cox proportional hazards regression models with comprehensive confounder adjustment. RESULTS: During a median follow-up of 10.6 years, 837 non-diabetic participants developed diabetes. We observed similar inverse associations with developing diabetes for VDBP (hazard ratio (HR) for lowest versus highest quintile: 1.37, 95% confidence interval (CI): 1.09, 1.72), total 25(OH)D (HR: 1.31, 95% CI: 1.03, 1.66), and "non-bioavailable" 25(OH)D (HR: 1.30, 95% CI: 1.02, 1.65). Associations were smaller and statistically insignificant for "bioavailable" and free 25(OH)D. However, associations of total "non-bioavailable", "bioavailable", and free 25(OH)D with incidence of diabetes were much stronger among, and essentially restricted to, participants with lower baseline HbA1c (≤6%) levels. CONCLUSIONS: This large prospective cohort study of older Caucasian adults, in agreement with results from randomized trials and Mendelian randomization studies, supports a protective effect of vitamin D against development of diabetes. The "free hormone theory" may not be relevant in this context. However, our results underline the importance of adequate vitamin D status among those who have not yet shown any sign of impaired glucose tolerance.

Vitamin D food fortification in European countries: the underused potential to prevent cancer deaths.

BACKGROUND: Meta-analyses of randomized controlled trials have shown that vitamin D supplementation reduces cancer mortality by 13%. Vitamin D fortification of foods may increase vitamin D levels in a similar manner as vitamin D supplementation and could achieve similar reductions in cancer mortality. Whereas some European countries already implemented widespread fortification of foods with vitamin D, in other countries only few or no foods are fortified. In this study, we estimated the reduction in cancer mortality presumably already achieved by current fortification policies in 2017 and the potential for further reductions if all countries had effective fortification. METHODS: We reviewed scientific literature, publicly available information, and contacted health authorities to obtain information on current vitamin D food fortification policies in 34 European countries. Together with country-specific cancer death statistics from Eurostat, information on life expectancy, and country-specific fortification policies, we used data from studies on supplementation and serum 25(OH)D increases and cancer mortality to estimate numbers of probably already prevented cancer deaths and numbers of potentially further preventable deaths and years of life lost. RESULTS: Current vitamin D fortification is estimated to prevent approximately 11,000 in the European Union and 27,000 cancer deaths in all European countries considered per year. If all countries considered here would implement adequate vitamin D fortification of foods, an estimated additional 129,000 cancer deaths (113,000 in the European Union) could be prevented, corresponding to almost 1.2 million prevented years of life lost (1.0 million in the EU) or approximately 9% of cancer deaths (10% in the EU). INTERPRETATION: Systematic fortification of foods might considerably reduce the burden of cancer deaths in Europe.

Vitamin D-binding protein, total, "nonbioavailable," bioavailable, and free 25-hydroxyvitamin D, and mortality in a large population-based cohort of older adults.

BACKGROUND: Epidemiological studies consistently find low concentrations of 25-hydroxyvitamin D (25(OH)D) in blood to be associated with increased mortality, and a recent large-scale Mendelian randomization study strongly supports a causal relationship among individuals with low vitamin D status. Evolving evidence suggested that bioavailable or free 25(OH)D may better predict mortality. We aimed to compare the prognostic values of vitamin D-binding protein (VDBP), total, bioavailable, complementary "nonbioavailable", and free 25(OH)D for total and cause-specific mortality in a large population-based cohort study of older adults from Germany. METHODS: Bioavailable, complementary "nonbioavailable", and free 25(OH)D concentrations were calculated among 5899 participants aged 50-75 years, based on serum concentrations of total 25(OH)D, VDBP, and albumin. The cohort was followed with respect to total and cause-specific mortality from recruitment in 2001-2002 up to the end of 2018. Multivariable Cox proportional hazards regression models were used to assess the associations between various vitamin D biomarkers and mortality, and further stratified by vitamin D status. RESULTS: During a median follow-up of 17.1 years, 1739 participants died, of whom 575, 584, and 94 died of cardiovascular diseases, cancer, and respiratory diseases, respectively. Very similar inverse associations with total mortality (hazard ratio (HR) per standard deviation decrease: 1.17, 95% confidence interval (CI): 1.11, 1.24 for total 25(OH)D; HR: 1.14, 95% CI: 1.08, 1.21 for bioavailable 25(OH)D; HR: 1.12, 95% CI: 1.06, 1.18 for free 25(OH)D) and cause-specific mortalities were seen for all biomarkers of vitamin D status. The strongest associations were consistently seen for respiratory mortality. These inverse associations were strongest among participants with low vitamin D levels (<50 nmol/L). No significant associations were seen between VDBP and mortality. CONCLUSIONS: Total, nonbioavailable, bioavailable, and free 25(OH)D showed very similar inverse associations with total and cause-specific mortality, which were strongest among those with low vitamin D status in this large population-based cohort.

Distribution and Determinants of Vitamin D-Binding Protein, Total, "Non-Bioavailable", Bioavailable, and Free 25-Hydroxyvitamin D Concentrations among Older Adults.

BACKGROUND: serum 25-hydroxyvitamin D (25(OH)D) ("total 25 OH(D)") is the most commonly used indicator of vitamin D status. However, 25(OH)D is mostly bound to the vitamin D binding protein (VDBP) or albumin in blood, and it has been suggested that the remaining bioavailable or free 25(OH)D may be more relevant for vitamin D associated health outcomes. We aimed to explore distributions and determinants of VDBP, total, bioavailable, complementary "non-bioavailable", and free 25(OH)D in a large cohort of older adults in Germany. METHODS: total 25(OH)D, VDBP, and albumin concentrations were measured in blood samples of 5899 men and women aged 50-75 years and used to calculate bioavailable (and complementary "non-bioavailable") and free 25(OH)D concentrations. Linear regression models were used to evaluate associations of potential determinants of the various vitamin D biomarkers. RESULTS: mean concentrations of VDBP, total, non-bioavailable, bioavailable, and free 25(OH)D were 323.6 µg/mL, 49.8 nmol/L, 43.4 nmol/L, 2.5 ng/mL, and 5.7 pg/mL, respectively. Seasonal variations were observed for all markers, with peak values in spring for VDBP and in summer for total, non-bioavailable, bioavailable, and free 25(OH)D. Consistent inverse associations were seen with age and body mass index for all markers, but divergent associations were seen with C-reactive protein. Strong variations by VDBP genotypes were seen for bioavailable and free 25(OH)D, and, in opposite direction for non-bioavailable 25(OH)D. CONCLUSION: commonalities and differences in determinants of various markers of vitamin D status were observed, which may help to enable a better understanding of their potential role for various vitamin D related health outcomes.

Potential of Vitamin D Food Fortification in Prevention of Cancer Deaths-A Modeling Study.

Meta-analyses of randomized controlled trials (RCTs) have estimated a 13% reduction of cancer mortality by vitamin D supplementation among older adults. We evaluated if and to what extent similar effects might be expected from vitamin D fortification of foods. We reviewed the literature on RCTs assessing the impact of vitamin D supplementation on cancer mortality, on increases of vitamin D levels by either supplementation or food fortification, and on costs of supplementation or fortification. Then, we derived expected effects on total cancer mortality and related costs and savings from potential implementation of vitamin D food fortification in Germany and compared the results to those for supplementation. In RCTs with vitamin D supplementation in average doses of 820-2000 IU per day, serum concentrations of 25-hydroxy-vitamin D increased by 15-30 nmol/L, respectively. Studies on food fortification found increases by 10-42 nmol/L, thus largely in the range of increases previously demonstrated by supplementation. Fortification is estimated to be considerably less expensive than supplementation. It might be similarly effective as supplementation in reducing cancer mortality and might even achieve such reduction at substantially larger net savings. Although vitamin D overdoses are unlikely in food fortification programs, implementation should be accompanied by a study monitoring the frequency of potentially occurring adverse effects by overdoses, such as hypercalcemia. Future studies on effectiveness of vitamin D supplementation and fortification are warranted.

Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study.

BACKGROUND: Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. METHODS AND FINDINGS: In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. CONCLUSIONS: Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.