scholarly journals 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts

2020 ◽  
Vol 66 (5) ◽  
pp. 676-685 ◽  
Author(s):  
Yunus Çolak ◽  
Shoaib Afzal ◽  
Børge G Nordestgaard
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Osteoporotic Fractures ◽  
Population Based ◽  
Hydroxyvitamin D ◽  
Mendelian Randomization Analysis ◽  
Hazard Ratios ◽  
Increased Risk ◽  
25 Hydroxyvitamin D ◽  
Randomization Analysis

Abstract Background Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis. Methods We genotyped 116 335 randomly chosen white Danish persons aged 20–100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries. Results During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97–1.09) for individuals with 25–49.9 nmol/L, 1.19 (1.10–1.28) for individuals with 12.5–24.9 nmol/L, and 1.39 (1.21–1.60) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00–1.15), 1.25 (1.13–1.37), and 1.49 (1.25–1.77) for osteoporotic fractures and 1.09 (0.98–1.22), 1.37 (1.18–1.57), and 1.41 (1.09–1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98–1.00) for total fractures, 0.99 (0.97–1.00) for osteoporotic fractures, and 0.98 (0.95–1.00) for fractures of hip or femur. Conclusions Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures.

scholarly journals Association of serum 25-hydroxyvitamin D with metabolic syndrome and type 2 diabetes: a one sample Mendelian randomization study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Xiao ◽  
Jingyi Lv ◽  
Shiyu Wang ◽  
Yang Zhou ◽  
Lunwen Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Mendelian Randomization ◽  
Middle Aged ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Randomization Analysis

Abstract Background Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China. Methods A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017–2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations. Results Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06–1.61) and of T2D of 1.32 (1.08–1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24–1.79) and of T2D of 1.47 (1.12–1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29–1.85) and of T2D of 1.54 (1.27–1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02–1.45) for T2D and 1.14 (95%CI: 1.03–1.43) for DBP. Conclusions This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.

scholarly journals Associations between vitamin D receptor genotypes and mortality in a cohort of older Dutch individuals

2011 ◽  
Vol 164 (1) ◽  
pp. 75-82 ◽  
Author(s):  
Renate T de Jongh ◽  
Paul Lips ◽  
Kelly J Rijs ◽  
Natasja M van Schoor ◽  
Mark H H Kramer ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Mortality Risk ◽  
Dna Analysis ◽  
Osteoporotic Fractures ◽  
Population Based ◽  
Vdr Polymorphism ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
Haplotype 1

ContextVitamin D receptor (VDR) polymorphisms are associated with a variety of diseases, which may translate into an effect on mortality.ObjectiveTo investigate the associations betweenVDRgene variants and mortality among older people.DesignThe analyses were conducted in a population-based, prospective cohort of the Longitudinal Aging Study Amsterdam. Adequate DNA analysis was performed in 923 men and women (≥65 years). We aimed to assess the associations between mortality and the VDR polymorphismFokI, three haplotypes of theCdx2andGATApolymorphisms, and three haplotypes of theBsmI,ApaI, andTaqIpolymorphisms.ResultsDuring the median follow-up of 10.7 years, 480 participants deceased (51%). Homozygosity for theCdx2–GATAhaplotype 1 allele was associated with a 30% higher mortality risk compared to the absence of alleles (hazard ratios (HR) 1.30, 95% confidence intervals (CI) 1.01–1.68). Adjustment for cardiovascular risk factors and 25-hydroxyvitamin D levels did not affect this HR. The number of copies of theCdx2–GATAhaplotype 1 allele was associated, although not significantly, with an increased risk of osteoporotic fractures (0 copies=reference, HR, 95% CI: 1 copy 2.01, 0.99–4.07 and 2 copies 1.81, 0.87–4.18). After adjustment for osteoporotic fractures, homozygosity for theCdx2–GATAhaplotype 1 allele was no longer associated with higher mortality risk (HR 1.08, 95% CI 0.83–1.41).ConclusionsTheCdx2–GATAhaplotype 1 allele was related to increased mortality risk, which may be partly explained by osteoporotic fractures. As the biological mechanism is uncertain and this study size is limited, our results should be interpreted as hypothesis generating.

scholarly journals Low Plasma 25-Hydroxyvitamin D and Risk of Tobacco-Related Cancer

2013 ◽  
Vol 59 (5) ◽  
pp. 771-780 ◽  
Author(s):  
Shoaib Afzal ◽  
Stig E Bojesen ◽  
Børge G Nordestgaard
Keyword(s):  
Vitamin D ◽  
Tobacco Smoke ◽  
Population Based ◽  
Lower Plasma ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Hazard Ratios ◽  
25 Hydroxyvitamin D ◽  
And Function

BACKGROUND Tobacco smoke chemicals may influence vitamin D metabolism and function, and conversely vitamin D may modify the carcinogenicity of tobacco smoke chemicals. We tested the hypothesis that lower plasma 25-hydroxyvitamin D [25(OH)D] is associated with a higher risk of tobacco-related cancer in the general population. METHODS A prospective population-based cohort of 9791 individuals from the Copenhagen City Heart Study who were free of cancer at baseline was followed from 1981–1983 until December 2008 with 100% complete follow-up. RESULTS During up to 28 years of follow-up, 1081 participants developed a tobacco-related cancer and 1506 developed other cancers. Decreasing 25(OH)D concentrations, subdivided by clinical categories or by seasonally adjusted percentile categories, were associated with increasing cumulative incidence of tobacco-related cancer (log-rank trend P = 2 × 10−6 and P = 5 × 10−9). Multivariable adjusted hazard ratios of tobacco-related cancer were 1.75 (95% CI, 1.33–2.30) for 25(OH)D <5 vs ≥20 ng/mL, and 2.07 (1.63–2.62) for ≤5th vs >66th percentile. Also, multivariable adjusted hazard ratios for a 50% reduction in 25(OH)D were 1.20 (1.13–1.28) for any tobacco-related cancer, 1.19 (95% CI, 1.09–1.31) for lung cancer, 1.44 (1.19–1.73) for head and neck cancer, 1.28 (1.06–1.54) for bladder cancer, 1.34 (1.04–1.73) for kidney cancer, and 0.95 (0.89–1.01) for other cancers. CONCLUSIONS Lower plasma 25(OH)D was associated with higher risk of tobacco-related cancers, but not with risk of other cancers.

scholarly journals The relative contributions of obesity, vitamin D, leptin, and adiponectin to multiple sclerosis risk: A Mendelian randomization mediation analysis

2021 ◽  
pp. 135245852199548 ◽  
Author(s):  
Adil Harroud ◽  
Despoina Manousaki ◽  
Guillaume Butler-Laporte ◽  
Ruth E Mitchell ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Mediation Analysis ◽  
Mendelian Randomization ◽  
Vitamin D Supplementation ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
Vitamin D Levels ◽  
25 Hydroxyvitamin D ◽  
Underlying Mechanisms

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

scholarly journals Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1987 ◽  
Author(s):  
Karl Michaëlsson ◽  
Håkan Melhus ◽  
Susanna Larsson
Keyword(s):  
Vitamin D ◽  
Major Depression ◽  
Mendelian Randomization ◽  
Vitamin D Insufficiency ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Single Nucleotide ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25 Hydroxyvitamin D

Whether vitamin D insufficiency is a contributing cause of depression remains unclear. We assessed whether serum 25-hydroxyvitamin D (S-25OHD) concentrations, the clinical marker of vitamin D status, were associated with major depression using Mendelian randomization. We used summary statistics data for six single-nucleotide polymorphisms significantly associated with S-25OHD concentrations in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) consortium and the corresponding data for major depression (n = 59,851 cases and 113,154 controls) from the Psychiatric Genomics Consortium. Genetically predicted S-25OHD concentrations were not associated with major depression. The odds ratio per genetically predicted one standard deviation decrease in S-25OHD concentrations was 1.02 (95% confidence interval 0.97–1.08; p = 0.44). The results of this study indicate that genetically lowered S-25OHD concentrations are not associated with increased risk of developing major depression.

scholarly journals Plasma 25-Hydroxyvitamin D Levels and Fracture Risk in a Community-Based Cohort of Elderly Men in Sweden

2010 ◽  
Vol 95 (6) ◽  
pp. 2637-2645 ◽  
Author(s):  
Håkan Melhus ◽  
Greta Snellman ◽  
Rolf Gedeborg ◽  
Liisa Byberg ◽  
Lars Berglund ◽  
...  
Keyword(s):  
Vitamin D ◽  
Uv Light ◽  
Winter Season ◽  
Community Dwelling ◽  
Reference Level ◽  
Blood Levels ◽  
Elderly Men ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25 Hydroxyvitamin D

Abstract Context: Blood levels of 25-hydroxyvitamin D [25(OH)D] is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. Objective: The objective of the study was to determine the threshold at which low plasma 25(OH)D levels are associated with fractures in elderly men and clarify the importance of low levels on total fracture burden. Design and Participants: In the Uppsala Longitudinal Study of Adult Men, a population-based cohort (mean age, 71 yr, n = 1194), we examined the relationship between 25(OH)D and risk for fracture. Plasma 25(OH)D levels were measured with high-pressure liquid chromatography-mass spectrometry. Setting: The study was conducted in the municipality of Uppsala in Sweden, a country with a high fracture incidence. Main Outcome Measure: Time to fracture was measured. Results: During follow-up (median 11 yr), 309 of the participants (26%) sustained a fracture. 25(OH)D levels below 40 nmol/liter, which corresponded to the fifth percentile of 25(OH)D, were associated with a modestly increased risk for fracture, multivariable-adjusted hazard ratio 1.65 (95% confidence interval 1.09–2.49). No risk difference was detected above this level. Approximately 3% of the fractures were attributable to low 25(OH)D levels in this population. Conclusions: Vitamin D insufficiency is not a major cause of fractures in community-dwelling elderly men in Sweden. Despite the fact that cutaneous synthesis of previtamin D during the winter season is undetectable at this northern latitude of 60°, only one in 20 had 25(OH)D levels below 40 nmol/liter, the threshold at which the risk for fracture started to increase. Genetic adaptations to limited UV light may be an explanation for our findings.

scholarly journals COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1714
Author(s):  
Habiba AlSafar ◽  
William B. Grant ◽  
Rafiq Hijazi ◽  
Maimunah Uddin ◽  
Nawal Alkaabi ◽  
...  
Keyword(s):  
Vitamin D ◽  
United Arab Emirates ◽  
Blood Levels ◽  
Vitamin D Status ◽  
Hospital Visit ◽  
Serum Samples ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
Multiethnic Population ◽  
25 Hydroxyvitamin D

Insufficient blood levels of the neurohormone vitamin D are associated with increased risk of COVID-19 severity and mortality. Despite the global rollout of vaccinations and promising preliminary results, the focus remains on additional preventive measures to manage COVID-19. Results conflict on vitamin D’s plausible role in preventing and treating COVID-19. We examined the relation between vitamin D status and COVID-19 severity and mortality among the multiethnic population of the United Arab Emirates. Our observational study used data for 522 participants who tested positive for SARS-CoV-2 at one of the main hospitals in Abu Dhabi and Dubai. Only 464 of those patients were included for data analysis. Demographic and clinical data were retrospectively analyzed. Serum samples immediately drawn at the first hospital visit were used to measure serum 25-hydroxyvitamin D [25(OH)D] concentrations through automated electrochemiluminescence. Levels < 12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and of death. Age was the only other independent risk factor, whereas comorbidities and smoking did not contribute to the outcomes upon adjustment. Sex of patients was not an important predictor for severity or death. Our study is the first conducted in the UAE to measure 25(OH)D levels in SARS-CoV-2-positive patients and confirm the association of levels < 12 ng/mL with COVID-19 severity and mortality.

scholarly journals Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

2018 ◽  
Vol 40 (4) ◽  
pp. 1109-1151 ◽  
Author(s):  
Roger Bouillon ◽  
Claudio Marcocci ◽  
Geert Carmeliet ◽  
Daniel Bikle ◽  
John H White ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Human Subjects ◽  
Osteoporotic Fractures ◽  
Vitamin D Supplementation ◽  
Current Evidence ◽  
Elderly Subjects ◽  
Vitamin D Status ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D

AbstractThe etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

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