Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis.

INTRODUCTION: A poor 25-hydroxyvitamin D (25(OH)D) status is a much replicated risk factor for developing multiple sclerosis (MS), and several vitamin D-associated single nucleotide polymorphisms (SNPs) have been associated with a higher risk of MS. However, studies on the benefit of vitamin D supplementation in MS show inconclusive results. Here, we explore whether vitamin D-associated SNPs and MS risk alleles confound serological response to vitamin D supplementation. METHODS: 34 participants from the SOLARIUM study consented to genotyping, of which 26 had vitamin D data available. The SOLARIUM study randomised relapsing-remitting MS patients to placebo or 14,000 IU vitamin D3 for 48 weeks. Participants were categorised as either 'carriers' or 'non-carriers' of the risk allele for 4 SNPs: two related to D binding protein (DBP) and associated with lower 25(OH)D levels (rs4588 and rs7041), and two related to vitamin D metabolism enzymes CYP27B1 and CYP24A1 and associated with a higher risk of MS (rs12368653; rs2248359, respectively). 25(OH)D levels were determined at baseline and after 48 weeks. RESULTS: The DBP-related SNPs showed no difference in 25(OH)D status at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 224.2 vs. 332.0 nmol/L, p = 0.013). For CYP related SNPs, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 304.1 vs. 152.0 nmol/L, p = 0.014). DISCUSSION: Vitamin D-related SNPs affect the serological response to high-dose vitamin D supplementation. The effects on more common doses of vitamin D, as well as the clinical consequence of this altered response, need to be investigated further.

Post hoc analysis of a randomised controlled trial: effect of vitamin D supplementation on circulating levels of desmosine in COPD.

BACKGROUND: Vitamin D supplementation lowers exacerbation frequency in severe vitamin D-deficient patients with COPD. Data regarding the effect of vitamin D on elastin degradation are lacking. Based on the vitamin's anti-inflammatory properties, we hypothesised that vitamin D supplementation reduces elastin degradation, particularly in vitamin D-deficient COPD patients. We assessed the effect of vitamin D status and supplementation on elastin degradation by measuring plasma desmosine, a biomarker of elastin degradation. METHODS: Desmosine was measured every 4 months in plasma of 142 vitamin D-naïve COPD patients from the Leuven vitamin D intervention trial (100 000 IU vitamin D3 supplementation every 4 weeks for 1 year). RESULTS: No significant association was found between baseline 25-hydroxyvitamin D (25(OH)D) and desmosine levels. No significant difference in desmosine change over time was found between the placebo and intervention group during the course of the trial. In the intervention arm, an unexpected inverse association was found between desmosine change and baseline 25(OH)D levels (p=0.005). CONCLUSIONS: Vitamin D supplementation did not have a significant overall effect on elastin degradation compared to placebo. Contrary to our hypothesis, the intervention decelerated elastin degradation in vitamin D-sufficient COPD patients and not in vitamin D-deficient subjects.

Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality.

BACKGROUND: Higher concentrations of 25-hydroxyvitamin D3 [25(OH)D3] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism. OBJECTIVES: We aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality. METHODS: The study population included 1169 newly diagnosed stage I-III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another. RESULTS: Serum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed. CONCLUSIONS: Our findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099.

Chemotherapy and vitamin D supplement use are determinants of serum 25-hydroxyvitamin D levels during the first six months after colorectal cancer diagnosis.

Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (ß-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (ß 4.0 nmol/L 95 %CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor. ClinicalTrials.gov Identifier: NCT03191110.

Vitamin D3 supplementation and neurofilament light chain in multiple sclerosis.

OBJECTIVES: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS: Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS: Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.

Correlation of different cellular assays to analyze T cell-related cytokine profiles in vitamin D3-supplemented patients with multiple sclerosis.

Different laboratory approaches have been exploited to analyze an effect of vitamin D3 supplements on T cell cytokine profiles in multiple sclerosis, with poorly reproducible results. We assessed the correlation between intra-cellular flowcytometry analysis of CD4 T cell-enriched CD3+CD8- lymphocytes after PMA/ionomycin stimulation directly ex-vivo or after 72 h pre-stimulation with anti-CD3, and cytokine levels excreted in culture supernatants. Pre-stimulation with anti-CD3 resulted in higher proportions of cells positive for IFN-γ, IL-17 A, IL-4, IL-10 and GM-CSF (all P < 0.001), but not TNF-α. Positive correlation between approaches was highly variable, but most eminent for IFN- γ and IL-4 (R = 0.608-0.612 and R = 0.677-0.777, resp., all P < 0.001). No effect of 16-weeks vitamin D3 supplements on any outcome was found except for a decreased TNF-α concentration in culture supernatants. Choice of immune-assay is, apparently, a relevant confounder for the reproducibility of individual studies.

Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis.

INTRODUCTION: Multiple sclerosis (MS) has been associated with both a poor vitamin D status and hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis. Since nuclear receptor ligands may regulate each other, we explored the association of vitamin D3 supplements with circadian cortisol levels in a double-blind and placebo-controlled supplementation study. METHODS: Female patients with relapsing-remitting MS received vitamin D3 supplements (4,000 IU/day; n = 22) or placebo (n = 19) during 16 weeks. Salivary cortisol levels, repeatedly measured during the day, and serum 25(OH)D levels were assessed before (T0) and after (T1) this treatment period. RESULTS: Median 25(OH)D levels at T1 were 139.9 (interquartile range 123.5-161.2) and 74.5 nmol/L (58.6-88.1) in the vitamin D3 and placebo group, respectively (p < 0.001). Comparisons within and between groups showed no differences in area under the curve (AUC) and slope of the cortisol day curve. Although the AUC of the cortisol awakening response (CAR, sampling each 15 min the first hour after awakening) showed a reduction over time in the vitamin D3 group [39.16 nmol/L (27.41-42.07) at T0 to 33.37 nmol/L (26.75-38.08) at T1] compared to the placebo group [33.90 nmol/L (25.92-44.61) at T0 to 35.00 nmol/L (25.46-49.23) at T1; p = 0.044], there was no significant difference in AUC of CAR at T1 corrected for baseline AUC of CAR (p = 0.066). CONCLUSION: Suppression of HPA-axis activity by vitamin D3 supplements in non-depressed MS patients may be best reflected by CAR as primary outcome measure. Further studies should address this interaction and its potential implications for the disease course of MS. REGISTRATION: This study was registered on ClinicalTrials.gov (NCT02096133) and EudraCT (2014-000728-97).