Effect of genetic factors on the response to vitamin D3 supplementation in the VIDARIS randomized controlled trial.

OBJECTIVES: Supplementation provides the best means of improving vitamin D status; however, individual responses vary partly owing to genetics. The aim of this study was to determine whether 28 single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were associated with differences in response to supplementation. METHODS: Participants (N = 313; n = 160 vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections Study), a double-blind, randomized controlled trial involving oral monthly supplementation of either vitamin D3 (200 000 IU each for the first 2 mo, thereafter 100 000 IU monthly) or placebo for 18 mo. Circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline and 2, 6, 12, and 18 mo, and vitamin D binding protein (Gc-globulin) and calculated free 25(OH)D concentrations at baseline and 2 mo were obtained. Multiple regression was used to model associations between genetic variants and 25(OH)D, Gc-globulin, and free 25(OH)D concentrations. RESULTS: SNPs within GC, CYP2 R1, and CYP27 B1 were associated with 25(OH)D concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than 2 mo of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations; however, there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25(OH)D concentrations in the supplemented arm. CONCLUSION: Only variants of GC were associated with 25(OH)D concentrations after supplementation. This effect was modest and disappeared after >2 mo of supplementation, suggesting it may be time/dose-dependent and saturable.

Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial.

OBJECTIVE: To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes. DESIGN: Opportunistic addition to an established randomised double blind placebo controlled trial. SETTING: Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage. PARTICIPANTS: 322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011. INTERVENTION: Participants were randomised to receive an oral dose of either 200,000 IU vitamin D3 monthly for two months then 100,000 IU monthly (n=161) or placebo (n=161) for a total of 18 months. MAIN OUTCOME MEASURE: This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of "psychological" adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial. RESULTS: 308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (χ(2) P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; χ(2) P=0.03). The number of psychological adverse events-such as fatigue, stress, anxiety, and insomnia-that participants reported at their usual monthly appointments was significantly higher after the earthquake (χ(2) P=0.007) but did not differ between treatment groups. CONCLUSION: In this trial, vitamin D supplementation did not reduce the adverse impact of earthquakes in healthy adults. Trial registration Australian New Zealand Clinical Trials Registry (anzctr.org.au) ACTRN12609000486224.

Long-term high-dose vitamin D3 supplementation and blood pressure in healthy adults: a randomized controlled trial.

Previous randomized controlled trials of vitamin D supplementation and blood pressure (BP) mainly have given vitamin D for short periods (<6 months) or at low doses (400 IU per day). This study aims to determine whether long-term high-dose vitamin D taken for 18 months lowers BP. Adults were recruited from a healthcare organization or university into a double-blind controlled trial and randomized to receive either vitamin D3 200 000 IU for 2 months followed by 100 000 IU monthly up to 18 months (n=161) or placebo (n=161). BP was measured at baseline, 5, and 18 months. Subjects had a mean (SD) age of 47.6 (9.7) years, 75% were women, and 94% were of European ancestry (white). Mean (SD) 25-hydroxyvitamin D3 changed from 73 (22) nmol/L at baseline to 124 (28) nmol/L at 18 months in the vitamin D group, and from 71 (22) nmol/L to 56 (22) nmol/L in the placebo group. Mean BP was similar for the vitamin D and placebo groups at baseline (123.4/76.3 versus 122.6/75.6 mm Hg; respectively). The mean change (95% confidence interval) in BP at 18 months minus baseline in the vitamin D group compared with placebo group was -0.6 (-2.8 to 1.6) mm Hg for systolic (P=0.61) and 0.5 (-1.1, 2.2) mm Hg for diastolic (P=0.53). Long-term vitamin D supplementation, which increased mean 25-hydroxyvitamin D3 concentration >100 nmol/L for 18 months, had no effect on systolic or diastolic BP in predominantly white, healthy adults without severe vitamin D deficiency. Beneficial effects on BP cannot be ruled out for other populations.

Comparison of two plasma urate assays in patients receiving vitamin C supplementation.

The aim of this study was to compare plasma urate (PU) concentrations using two different assays in patients receiving vitamin C supplementation. PU was measured using two routinely available enzymatic uricase methods: (1) uric acid plus method (ascorbate oxidase assay), and (2) uric acid method (non-ascorbate oxidase assay). Twenty patients receiving allopurinol were randomised to an increase in allopurinol dose or commence vitamin C 500  mg/d on a 1:1 ratio. Twenty patients not receiving allopurinol were randomised to start allopurinol or vitamin C 500  mg/d on a 1:1 ratio. Trough fasting samples for plasma ascorbate and urate were measured weekly until week 8. There was no significant difference in the mean PU measured by the two assays. In patients not receiving supplemental vitamin C the mean PU concentrations were identical for both assays. For patients receiving supplemental vitamin C the mean PU concentrations for the ascorbate oxidase assay was 0.525  mmol/L (SE 0.034) and for the non-ascorbate oxidase assay 0.510  mmol/L (SE 0.033), p = 0.079.There is a small non-significant difference in measured PU in patients receiving supplemental vitamin C between the two assays. The assay which does not include ascorbate oxidase results in consistently lower PU concentrations compared to the assay which includes ascorbate oxidase.

Falsely elevated plasma selenium due to gadolinium contrast interference: a novel solution to a preanalytical problem.

BACKGROUND: Trace elements are commonly measured by inductively coupled mass spectrometry (ICP-MS). A 30-year-old man had a plasma selenium (Se) concentration on ICP-MS of 66 µmol/L (reference interval 0.45-1.40), a potentially lethal level, despite no history of Se exposure or toxicity symptoms. He had earlier undergone magnetic resonance imaging with a gadolinium (Gd) contrast agent, which is known to interfere with Se on ICP-MS. We aimed to adjust our method by monitoring a second Se isotope that is unaffected by Gd to detect this preanalytical interference. METHODS: Plasma samples referred for trace metal testing had Se measured on ICP-MS (monitoring (78)Se), which we modified to also monitor a second isotope ((82)Se). The modified method was then applied to a specimen with known Gd contamination. RESULTS: Plasma Se results (n = 41) derived from monitoring the two different Se isotopes were similar with a good correlation (R (2 )= 0.991) over a range of 0.23-2.21 µmol/L. On repeat analysis, our patient had a Se concentration of 65 µmol/L using the (78)Se isotope but only 1.43 µmol/L using (82)Se. CONCLUSION: To avoid reporting a falsely elevated plasma Se result, we suggest that Se analysis by ICP-MS should include a second Se isotope for monitoring, that is not subject to Gd interference.

Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.

CONTEXT: Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive. OBJECTIVE: To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand. INTERVENTION: Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months. MAIN OUTCOME MEASURES: The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes. RESULTS: The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels. CONCLUSION: In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609000486224.

Pharmacokinetic comparison of a generic coenzyme Q10 solubilizate and a formulation with soybean phytosterols.

Coenzyme Q10 (CoQ10) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ10 solubilized in low-dose soybean phytosterols (SterolQ10) with a generic CoQ10 solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ10, as SterolQ10 or generic CoQ10, with a two-week washout between treatments. Plasma CoQ10 was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ10 or SterolQ10 for 4 weeks. Fasting plasma CoQ10 levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80-0.96), respectively. Four-weeks of CoQ10 resulted in a comparable twofold increase in CoQ10 levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ10 and phytosterol formulation, SterolQ10, showed bioequivalence to the generic CoQ10 following a single CoQ10 dose, and demonstrated comparable bioavailability following multiple dose administration.

Relationship between plasma coenzyme Q10, asymmetric dimethylarginine and arterial stiffness in patients with phenotypic or genotypic familial hypercholesterolemia on long-term statin therapy.

OBJECTIVE: We investigated whether statin-treated heterozygous familial hypercholesterolemic (FH) patients have lower plasma coenzyme Q(10) (CoQ(10)) levels than low-density lipoprotein receptor (LDLR) mutation negative FH patients on equivalent statin doses, and whether lower CoQ(10) concentrations are associated with increased arterial stiffness. METHODS: Thirty LDLR mutation negative patients with clinical FH and 30 mutation positive FH patients matched for gender, statin duration and dose, and a further 30 controls were studied. Plasma CoQ(10) and asymmetric dimethylarginine (ADMA) levels were measured by HPLC and the augmentation index by pulse wave analysis. RESULTS: Plasma CoQ(10) levels, and the ratios of CoQ(10) to total cholesterol and LDL-cholesterol were similar in treated FH patients with identified LDLR mutations to mutation negative patients on equivalent doses of statin therapy (p>0.05). CoQ(10) and lipid levels were also comparable to controls not using any lipid modifying treatment. Arterial stiffness was higher in mutation negative patients (p=0.04) and there was a trend for an increase in mutation positive patients (p=0.09). ADMA was higher in the mutation positive group (p<0.01). The augmentation index corrected for age, blood pressure, and heart rate, was negatively correlated with plasma CoQ(10) within FH patients (p<0.05). CONCLUSION: Long-term, high-dose statin therapy does not lead to subnormal CoQ(10) concentrations in patients with phenotypic or genotypic FH. Arterial stiffness is elevated in FH patients compared to untreated controls, and low CoQ(10) levels are associated with increased arterial stiffness. CoQ(10) supplementation trials are warranted in FH patients.

Coenzyme Q10; an adjunctive therapy for congestive heart failure?

Coenzyme Q10 (CoQ10) is essential for electron transport within the mitochondria and hence for ATP generation and cellular energy production. We recently demonstrated that plasma levels of CoQ10 are an independent predictor of survival in a cohort of 236 patients with chronic heart failure (CHF) followed for a median of 2.69 years. This is consistent with previous studies which have shown myocardial CoQ10 depletion in CHF, and correlated with the severity of the underlying disorder. Several intervention studies have been undertaken with CoQ10 in CHF, including randomized controlled trials with mostly positive outcomes in relation to improvement in plasma levels of CoQ10. A meta-analysis showed that CoQ10 resulted in an improvement in ejection fraction of 3.7% (95%CI 1.59-5.77) and the mean increase in cardiac output was 0.28 L/minute (95%CI 0.03-0.53). In a subgroup analysis, studies with patients not taking ACE inhibitors found a 6.7% increase in ejection fraction. The ongoing Q-SYMBIO trial will address whether CoQ10 supplementation improves survival in CHF patients. CoQ10 depletion may also be a contributory factor for why statin intervention has not improved outcomes in CHF. There is an emerging evidence base in support of CoQ10 as an adjunctive therapy in CHF.

Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia.

Myalgia is the most frequently reported adverse side effect associated with statin therapy and often necessitates reduction in dose, or the cessation of therapy, compromising cardiovascular risk management. One postulated mechanism for statin-related myalgia is mitochondrial dysfunction through the depletion of coenzyme Q(10), a key component of the mitochondrial electron transport chain. This pilot study evaluated the effect of coenzyme Q(10) supplementation on statin tolerance and myalgia in patients with previous statin-related myalgia. Forty-four patients were randomized to coenzyme Q(10) (200 mg/day) or placebo for 12 weeks in combination with upward dose titration of simvastatin from 10 mg/day, doubling every 4 weeks if tolerated to a maximum of 40 mg/day. Patients experiencing significant myalgia reduced their statin dose or discontinued treatment. Myalgia was assessed using a visual analogue scale. There was no difference between combined therapy and statin alone in the myalgia score change (median 6.0 [interquartile range 2.1 to 8.8] vs 2.3 [0 to 12.8], p = 0.63), in the number of patients tolerating simvastatin 40 mg/day (16 of 22 [73%] with coenzyme Q(10) vs 13 of 22 [59%] with placebo, p = 0.34), or in the number of patients remaining on therapy (16 of 22 [73%] with coenzyme Q(10) vs 18 of 22 [82%] with placebo, p = 0.47). In conclusion, coenzyme Q(10) supplementation did not improve statin tolerance or myalgia, although further studies are warranted.