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Vitamin D supplementation is widely used. However, there is no consensus on the use and dosage of this supplement and the existing recommendations arise from studies based on the benefits that this nutrient can facilitate in bones. In addition, individual genetics can influence the response to supplementation, therefore, research involving monozygotic twins aims to reduce these differences in phenotypic responses. The objective of this randomised controlled study is to examine the effect of vitamin D supplementation on body composition and the expression of the vitamin D receptor ( VDR ) mRNA. An intervention was performed through supplementation with cholecalciferol at the concentration of 2000 IU in 90 healthy adult monozygotic twins (male or female pairs) for 2 months. The findings showed that serum vitamin D concentration increased by 65% and VDR gene expression sixty times ( p  = 0.001). Changes in body composition parameters were observed regarding body fat and lean mass. Our results indicate that an increase in serum vitamin D concentration may have potential therapeutic implications.

ObjectiveWe assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival.DesignWe sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response.ResultsSerial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1–2). CRP peaked 3–5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I–III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77).ConclusionsCRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.

Vitamin D (vitD) deficiency (25-hydroxy-vitamin D < 50 nmol/L) is common in pregnancy and associated with an increased risk of adverse pregnancy outcomes. High-dose vitD supplementation is suggested to improve pregnancy health, but there is limited knowledge about the effects on placental vitD transport and metabolism and the vitD status of newborns. Comparing the current standard maternal supplementation, 10 µg/day to a 90 µg vitD supplement, we investigated placental gene expression, maternal vitD transport and neonatal vitD status. Biological material was obtained from pregnant women randomized to 10 µg or 90 µg vitD supplements from week 11–16 onwards. Possible associations between maternal exposure, neonatal vitD status and placental expression of the vitD receptor (VDR), the transporters (Cubilin, CUBN and Megalin, LRP2) and the vitD-activating and -degrading enzymes (CYP24A1, CYP27B1) were investigated. Maternal vitD-binding protein (VDBP) was determined before and after supplementation. Overall, 51% of neonates in the 10 µg vitD group were vitD-deficient in contrast to 11% in the 90 µg group. High-dose vitD supplementation did not significantly affect VDBP or placental gene expression. However, the descriptive analyses indicate that maternal obesity may lead to the differential expression of CUBN, CYP24A1 and CYP27B1 and a changed VDBP response. High-dose vitD improves neonatal vitD status without affecting placental vitD regulation.

Background and aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic problem which can lead to irreversible liver fibrosis. It has been shown that vitamin D and its receptors contribute to fibrogenic pathways in the liver. However, the effect of vitamin D supplementation on liver fibrosis related factors have not been examined. This double blinded placebo controlled clinical trial was designed to investigate the effects on vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients. Methods Forty six MASLD patients after block matching for sex and BMI were randomly assigned to receive 4000 IU/d vitamin D or placebo for 12 weeks. Weight, height and waist circumference were measured. Serum fibrogenic microRNAs, laminin, collagen type IV, hyaluronic acid, vitamin D, VDR, PTH, blood fasting glucose, serum fasting insulin, lipid profile, ALT and AST were determined at the baseline and at the end of the trial. Insulin resistance and insulin sensitivity were calculated using the HOMA-IR and QUICKI equation. Results Supplementation with vitamin D for 12 weeks led to the significant increases in serum 25(OH) vitamin D, VDR and HDL-C compared to placebo ( P  < 0.001, P  = 0.008 and P  < 0.001). There were significant decreases in ALT, AST, FBS and LDL-C levels in the vitamin D group as compared to the placebo ( P  < 0.05). Laminin and hyaluronic acid concentrations were significantly decreased in the vitamin D group as compared to the placebo group, by -10.6 and − 28.7 ng/mL, respectively. Supplementation with vitamin D for 12 weeks resulted in a significant lower MiR-21 and MiR-122 gene expressions compared to the placebo group ( P  = 0.01 and P  < 0.001, respectively). Discussion As the first randomized controlled trial on the effect of vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients, we found a significant reduction in some liver fibrogenic factors, in liver transaminases and corresponding changes in some fibrosis-related MiRs and some metabolic factors. Further clinical trials with larger sample sizes and direct measures of liver fibrosis are needed to confirm these findings. Trial registration number (available at: http://www.irct.ir , identifier: IRCT201405251485N13), Registration date: 14-03-2017.

Although vitamin D (VD) is known to have multiple effects on the skin and immunity, its effects on atopic dermatitis (AD) severity remain unclear. We investigated whether oral cholecalciferol (VD3) supplementation changes stratum corneum expression of the vitamin D receptor ( vdr ), and the epidermal alarmins Cathelicidin Antimicrobial Peptide ( camp /LL-37) and Thymic Stromal Lymphopoietin ( tslp ) in children with AD. We conducted an open-label supplementation study with weekly oral VD3 for six weeks in children with AD. Serum 25-hydroxyvitamin D (25OHD), lesional Staphylococcus aureus colonization, and AD severity evaluated by SCORAD index were evaluated before and after supplementation. Tape stripping (TS) was performed on non-lesional and lesional skin to measure mRNA expression of vdr , camp , and tslp through RT-qPCR and LL-37 peptide by ELISA. Twenty-two children with moderate–severe AD received weekly oral VD3 for six weeks. Total serum 25OHD increased from 45.1 ± 23 to 93.5 ± 24.3 nmoL/L ( p  < 0.0001), while SCORAD decreased from 41.4 ± 13.5 to 31.5 ± 15.8 ( p  < 0.0001). After treatment, epidermal gene expression of camp increased significantly in non-lesional ( p  = 0.014) and lesional ( p  = 0.0007) tape stripping samples, while vdr only increased in lesional skin samples ( p  < 0.0001) . LL-37 peptide increased significantly only in lesional skin samples ( p  = 0.008). Gene expression of tslp did not change after oral VD3 treatment. In children with AD, oral VD3 supplementation was associated with improved VD status and AD severity, as well as increased VDR and Cathelicidin expression in lesional skin, which provide mechanistic clues on its effects.

PurposeThe aim of the study was to evaluate markers of oxidative stress and vitamin D receptor in paraspinal muscles in low back pain patients with vitamin D deficiency, with normal level of vitamin D, and after 5 weeks of vitamin D supplementation.MethodsPatients were divided into three groups: supplemented (SUP) with vitamin D, placebo with normal concentration of vitamin D (SUF), and the placebo group with vitamin D deficiency (DEF). The concentration of serum vitamin D was measured before and after the supplementation with vitamin D (3200 IU/ day for 5 weeks). Markers of lipid and protein peroxidation, the activity of antioxidant enzymes, and protein content of vitamin D receptor was determined in multifidus muscle of patients.ResultsVitamin D supplementation increased serum level of 25(OH)D3 (p < 0.001). In paraspinal muscle level of 8-isoprostanes and protein carbonyls was higher in DEF group as compared to the SUP group (p < 0.05). Antioxidant enzyme activity and vitamin D receptor in paraspinal muscle altered between the groups with different serum vitamin D concentration. The cytosolic superoxide dismutase and glutathione peroxidase activities were significantly higher in DEF group as compared to the SUP group (p < 0.05).ConclusionsAn attenuation of markers of free radical damage of lipids and proteins was observed in participants supplemented with Vitamin D. Antioxidant enzyme activities in skeletal muscle differ among patients with different serum vitamin D concentration. Monitoring oxidative stress and VDR protein content might be useful for future studies on the mechanism(s) of vitamin D action in muscle.

Vitamin D receptor [VDR] expression promotes LL37 expression, possibly contributing to host defense. The hypothesis was that an increase in 25 hydroxyvitamin D [25vitD] could lead to enhanced VDR expression and increased LL-37 production, thereby contributing to improved prognosis in critically ill patients. Methods: A nonblinded, randomized controlled trial was conducted. A total of 207 patients admitted to ICU with severe SARS-CoV-2 pneumonia were included and received different doses of cholecalciferol (500 MU, 3 MU/day, no cholecalciferol) during their ICU and hospital stay. 25vitD levels as well as LL37 and monocytes’ VDR gene expression were evaluated on admission and after. Clinical evolution, ICU mortality, hospital mortality, and 60-day mortality were evaluated. Results: The median age was 57.7 years and the majority of patients were Caucasian [87.4%] and male [70.5%]. There was a significant difference in 25vitD levels between groups on the third [p = 0.002] and seventh [p < 0.001] days. Patients supplemented with 500 MU of cholecalciferol had a very significant increase in monocytes’ VDR gene expression and showed a better clinical evolution in the ICU, with a significant correlation to evolution factors. Higher LL37 on admission had a significant negative association with hospital and ICU mortality, lost after adjustment for comorbidities to a nearly significant association with ICU, hospital, and 60-day mortality. Conclusion: Supplementation with higher doses of cholecalciferol may contribute to a significant increase in 25vitD levels but not in LL37 levels. Higher LL37 levels on admission may be related to a decrease in ICU, hospital, and 60-day mortality. VDR gene expression in monocytes is much higher in patients supplemented with higher doses of cholecalciferol.

Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms. During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7-10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2-3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1-3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1-5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60% approximately 70% lower risks of total and aggressive prostate cancer. Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.

PURPOSE: Laboratory studies have suggested that vitamin D inadequacy may be implicated in development of hypertension. Evidence from epidemiologic studies remains limited. We aim to examine the prospective associations of circulating vitamin D metabolites, vitamin D receptor (VDR) gene polymorphisms, and their interaction with risk of hypertension. METHODS: We conducted prospective analyses among 1,211 US men that were free of baseline hypertension and had baseline plasma 25hydroxy-vitamin D (25(OH)D) or 1,25dihydroxy-vitamin D (1,25(OH)₂D) measured and VDR BsmI or FokI polymorphisms genotyped. RESULTS: During 15.3-year follow-up, 695 men developed incident hypertension. After multivariable adjustment, the hazard ratios (HRs) and 95 % CIs for hypertension across increasing quartiles of plasma vitamin D metabolites were 1.00 (ref), 0.94 (0.69–1.27), 0.69 (0.50–0.96), and 0.82 (0.60–1.13) for 25(OH)D (p, trend: 0.43), and 1.00, 0.92 (0.66–1.27), 1.12 (0.82–1.54), and 1.19 (0.86–1.63) for 1,25(OH)₂D (p, trend: 0.16). Compared with carriers of VDR BsmI bb, carriers of bB or BB had a HR of 1.25 (1.04–1.51) for hypertension. For VDR FokI polymorphism, compared with carriers of FF and Ff combined, carriers of ff had a HR of 1.32 (1.03–1.70). The relation between plasma 25(OH)D and risk of hypertension did not differ by VDR BsmI and FokI polymorphisms. CONCLUSIONS: In a prospective cohort of men, we found suggestive evidence for an inverse association between plasma 25(OH)D and risk of hypertension. We also found associations between VDR BsmI and FokI polymorphisms with hypertension risk. More research is needed to further determine the role of vitamin D in hypertension prevention.

In a longitudinal study including 642 healthy 8–11-year-old Danish children, we investigated associations between vitamin D dependent SNP and serum 25-hydroxyvitamin D (25(OH)D) concentrations across a school year (August–June). Serum 25(OH)D was measured three times for every child, which approximated measurements in three seasons (autumn, winter, spring). Dietary and supplement intake, physical activity, BMI and parathyroid hormone were likewise measured at each time point. In all, eleven SNP in four vitamin D-related genes: Cytochrome P450 subfamily IIR1 (CYP2R1); 7-dehydrocholesterol reductase/nicotinamide adenine dinucleotide synthetase-1(DHCR7/NADSYN1); group-specific complement (GC); and vitamin D receptor were genotyped. We found minor alleles of CYP2R1 rs10500804, and of GC rs4588 and rs7041 to be associated with lower serum 25(OH)D concentrations across the three seasons (all P<0·01), with estimated 25(OH)D differences of −5·8 to −10·6 nmol/l from major to minor alleles homozygosity. In contrast, minor alleles homozygosity of rs10741657 and rs1562902 in CYP2R1 was associated with higher serum 25(OH)D concentrations compared with major alleles homozygosity (all P<0·001). Interestingly, the association between season and serum 25(OH)D concentrations was modified by GC rs7041 (P interaction=0·044), observed as absence of increase in serum 25(OH)D from winter to spring among children with minor alleles homozygous genotypes compared with the two other genotypes of rs7041 (P<0·001). Our results suggest that common genetic variants are associated with lower serum 25(OH)D concentrations across a school year. Potentially due to modified serum 25(OH)D response to UVB sunlight exposure. Further confirmation and paediatric studies investigating vitamin D-related health outcomes of these genotypic differences are needed.