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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.
Chen, LJ, Sha, S, Stocker, H, Brenner, H, Schöttker, B
The American journal of clinical nutrition. 2024;(4):1052-1064
Abstract
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.
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A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.
Giaccherini, M, Rende, M, Gentiluomo, M, Corradi, C, Archibugi, L, Ermini, S, Maiello, E, Morelli, L, van Eijck, CHJ, Cavestro, GM, et al
Mutagenesis. 2024
Abstract
Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.
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Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.
, , Magnussen, C, Ojeda, FM, Leong, DP, Alegre-Diaz, J, Amouyel, P, Aviles-Santa, L, De Bacquer, D, Ballantyne, CM, Bernabé-Ortiz, A, et al
The New England journal of medicine. 2023;(14):1273-1285
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BACKGROUND Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).
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Real-world evidence for the effectiveness of vitamin D supplementation in reduction of total and cause-specific mortality.
Sha, S, Nguyen, TMN, Kuznia, S, Niedermaier, T, Zhu, A, Brenner, H, Schöttker, B
Journal of internal medicine. 2023;(3):384-397
Abstract
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.
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Effects of vitamin D supplementation on inflammatory response in patients with cancer and precancerous lesions: Systematic review and meta-analysis of randomized trials.
Gwenzi, T, Zhu, A, Schrotz-King, P, Schöttker, B, Hoffmeister, M, Brenner, H
Clinical nutrition (Edinburgh, Scotland). 2023;(7):1142-1150
Abstract
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.
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Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.
, , Grams, ME, Coresh, J, Matsushita, K, Ballew, SH, Sang, Y, Surapaneni, A, Alencar de Pinho, N, Anderson, A, Appel, LJ, et al
JAMA. 2023;(13):1266-1277
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IMPORTANCE Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). CONCLUSIONS AND RELEVANCE In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.
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Prognostic Value of Post-Operative C-Reactive Protein-Based Inflammatory Biomarkers in Colorectal Cancer Patients: Systematic Review and Meta-Analysis.
Gwenzi, T, Zhu, A, Schrotz-King, P, Schöttker, B, Hoffmeister, M, Edelmann, D, Brenner, H
Clinical epidemiology. 2023;:795-809
Abstract
Post-operative inflammation in cancer patients can be modulated by drugs and diets, but evidence on its prognostic role, which would be crucial for personalized treatment and surveillance schemes, remains rather limited. We aimed to systematically review and meta-analyse studies on the prognostic value of post-operative C-reactive protein (CRP)-based inflammatory biomarkers among patients with colorectal cancer (CRC) (PROSPERO#: CRD42022293832). PubMed, Web of Science and Cochrane databases were searched until February 2023. Studies reporting associations between post-operative CRP, Glasgow Prognostic Score (GPS) or modified Glasgow Prognostic Score (mGPS) with overall survival (OS), CRC-specific survival (CSS) and recurrence-free survival (RFS) were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) for the predictor-outcome associations were pooled using R-software, version 4.2. Sixteen studies (n = 6079) were included in the meta-analyses. Elevated post-operative CRP was a predictor of poor OS, CSS and RFS compared with low CRP levels [HR (95% CI): 1.72 (1.32-2.25); 1.63 (1.30-2.05); 2.23 (1.44-3.47), respectively]. A unit increase in post-operative GPS predicted poor OS [HR (95% Cl): 1.31 (1.14-1.51)]. Moreover, a unit increase in post-operative mGPS was associated with poor OS and CSS [HR (95% Cl): 1.93 (1.37-2.72); 3.16 (1.48-6.76), respectively]. Post-operative CRP-based inflammatory biomarkers have a significant prognostic role for patients with CRC. Prognostic value of these easy-to-obtain routine measurements thereby seems to outperform most of the much more complex blood- or tissue-based predictors in the current focus of multi-omics-based research. Future studies should validate our findings, establish optimal time for biomarker assessment and determine clinically useful cut-off values of these biomarkers for post-operative risk-stratification and treatment-response monitoring.
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Vitamin D-Binding Protein, Bioavailable, and Free 25(OH)D, and Mortality: A Systematic Review and Meta-Analysis.
Zhu, A, Kuznia, S, Boakye, D, Schöttker, B, Brenner, H
Nutrients. 2022;(19)
Abstract
INTRODUCTION Observational studies reported inverse associations between serum total 25-hydroxyvitamin D (25(OH)D) concentrations and mortality. Evolving evidence indicated, however, that bioavailable or free 25(OH)D may be even better predictors of mortality. We conducted a systematic review and meta-analysis to summarize the epidemiological evidence on associations of vitamin D-binding protein (VDBP), albumin-bound, bioavailable, and free 25(OH)D, with mortality. METHODS We systematically searched PubMed and Web of Science, up to 27 May 2022. Predictors of interest included serum or plasma concentrations of VDBP, albumin-bound, bioavailable, and free 25(OH)D. Assessed health outcomes were all-cause and cause-specific mortality. We included studies reporting associations between these biomarkers and mortality outcomes. We applied random-effects models for meta-analyses to summarize results from studies assessing the same vitamin D biomarkers and mortality outcomes. RESULTS We identified twelve eligible studies, including ten on VDBP, eight on bioavailable 25(OH)D, and eight on free 25(OH)D. No study reported on albumin-bound 25(OH)D and mortality. In meta-analyses, the highest levels of bioavailable and free 25(OH)D were associated with 37% (hazard ratio (HR): 0.63, 95% confidence interval (CI): 0.46, 0.87), and 29% (HR: 0.71, 95% CI: 0.53, 0.97) decrease in all-cause mortality, respectively, compared with the lowest levels. These estimates were similar to those for total 25(OH)D (HR: 0.67, 95% CI: 0.56, 0.80) observed in the same studies. Higher VDBP levels were associated with lower all-cause mortality in cancer patient cohorts. However, no such association was observed in general population cohorts. CONCLUSIONS Similar inverse associations of total, bioavailable, and free 25(OH)D with mortality suggest that bioavailable and free 25(OH)D do not provide incremental value in predicting mortality.
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.
Winkler, TW, Rasheed, H, Teumer, A, Gorski, M, Rowan, BX, Stanzick, KJ, Thomas, LF, Tin, A, Hoppmann, A, Chu, AY, et al
Communications biology. 2022;(1):580
Abstract
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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Vitamin D food fortification in European countries: the underused potential to prevent cancer deaths.
Niedermaier, T, Gredner, T, Kuznia, S, Schöttker, B, Mons, U, Lakerveld, J, Ahrens, W, Brenner, H, ,
European journal of epidemiology. 2022;(4):309-320
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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.