Cord Serum Calcitriol Inversely Correlates with Maternal Blood Pressure in Urinary Tract Infection-Affected Pregnancies: Sex-Dependent Immune Implications.

Urinary tract infections (UTI) during pregnancy are frequently associated with hypertensive disorders, increasing the risk of perinatal morbidity. Calcitriol, vitamin D3's most active metabolite, has been involved in blood pressure regulation and prevention of UTIs, partially through modulating vasoactive peptides and antimicrobial peptides, like cathelicidin. However, nothing is known regarding the interplay between placental calcitriol, cathelicidin, and maternal blood pressure in UTI-complicated pregnancies. Here, we analyzed the correlation between these parameters in pregnant women with UTI and with normal pregnancy (NP). Umbilical venous serum calcitriol and its precursor calcidiol were significantly elevated in UTI. Regardless of newborn's sex, we found strong negative correlations between calcitriol and maternal systolic and diastolic blood pressure in the UTI cohort (p < 0.002). In NP, this relationship was observed only in female-carrying mothers. UTI-female placentas showed higher expression of cathelicidin and CYP27B1, the calcitriol activating-enzyme, compared to male and NP samples. Accordingly, cord-serum calcitriol from UTI-female neonates negatively correlated with maternal bacteriuria. Cathelicidin gene expression positively correlated with gestational age in UTI and with newborn anthropometric parameters. Our results suggest that vitamin D deficiency might predispose to maternal cardiovascular risk and perinatal infections especially in male-carrying pregnancies, probably due to lower placental CYP27B1 and cathelicidin expression.

Expression Analysis of VDR-Related LncRNAs in Autism Spectrum Disorder.

Vitamin D receptor (VDR) signaling has been reported to affect neurodevelopment, thus participating in the risk of autism spectrum disorder (ASD). We have measured expression amounts of VDR, CYP27B1, and two related long non-coding RNAs, namely SNHG6 and LINC00511, in the circulation of ASD patients compared with normal controls. Expression of CYP27B1 was remarkably higher in ASD cases compared with controls (posterior beta = 2.38, SE = 0.46, adjusted P value < 0.0001, 95% credible interval (CrI) for beta = [1.49, 3.27]). Level of SNHG6 was lower in ASD cases compared with controls (posterior beta = - 0.791, SE = 0.24, adjusted P value = 0.029, 95% CrI for beta = [- 1.27, - 0.33]). Expression levels of VDR and LINC00511 were similar between ASD cases and controls (P values = 0.97 and 0.46, respectively). Expressions of VDR, CYP27B1, SNHG6, and LINC00511 were not correlated with age of children. However, significant correlations were perceived between expressions of CYP27B1 and LINC00511 (r = 0.47, P < 0.0001), VDR and CYP27B1 (r = 0.42, P < 0.0001), and VDR and SNHG6 (r = 0.32, P < 0.0001). Therefore, these results imply dysregulation of a number of VDR-related genes in ASD patients.

Lower placental 25-hydroxyvitamin D3 (25(OH)D3) and higher placental CYP27B1 and 25(OH)D3 ratio in preterm birth.

Neonatal mortality rates in Indonesia are still at an alarming rate, with preterm birth as one of the causes. Nutritional deficiencies such as low level of vitamin D is suspected to be the risk factors of preterm birth but still a little knowledge about it. Vitamin D metabolism includes 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), as the inactive and active form, with the help of 1α-hydroxylase (CYP27B1) enzyme. Our study aims to determine the differences of 25(OH)D3, 1,25(OH)2D3 and CYP27B1 enzyme in term and preterm birth. A cross-sectional study was performed in Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia, in January-June 2017. The blood sample was taken soon after delivery, to examine maternal 25(OH)D3 and 1,25(OH)2D3 in serum and tissue placenta, as well as placental CYP27B1 enzyme. Statistical analysis using SPPS version 20 was used to find significances. There were a total of sixty subjects in this study, with term-preterm birth group ratio 1:1. We found that placental 25(OH)D3 was significantly low (P = 0⋅001), and CYP27B1/25(OH)D3 ratio was high in preterm birth. Also, there were significant negative correlations found in CYP27B1 level and both placental 25(OH)D3 (r 0⋅481, P < 0⋅001) and 1,25(OH)2D3 (r -0⋅365, P = 0⋅004) levels. Our study concludes that preterm birth showed lower placental 25(OH)D3 status, and higher CYP27B1/25(OH)D3 ratio compared to term pregnancy.

Vitamin D-related genes and cardiometabolic markers in healthy children: a Mendelian randomisation study.

Observational studies show associations between low serum 25-hydroxyvitamin D (25(OH)D) and cardiometabolic risk markers. This Mendelian randomisation study examined associations between cardiometabolic markers in children and SNP in genes related to vitamin D metabolism (DHCR7; group-specific complement (GC); cytochrome P450 subfamily IIR1 (CYP2R1); and CYP24A1) and action (CYP27B1 and VDR). In 699 healthy 8-11-year-old children, we genotyped eleven SNP. We generated a genetic risk score based on SNP associated with low 25(OH)D and investigated associations between this and blood pressure, plasma lipids and insulin. Furthermore, we examined whether SNP related to vitamin D actions modified associations between 25(OH)D and the cardiometabolic markers. All GC and CYP2R1 SNP influenced serum 25(OH)D. A risk score based on four of the six SNP was associated with 3·4 (95 % CI 2·6, 4·2) mmol/l lower 25(OH)D per risk allele (P < 0·001), but was not associated with the cardiometabolic markers. However, interactions were indicated for the three VDR SNP (Pinteraction < 0·081) on associations between 25(OH)D and TAG, systolic blood pressure and insulin, which all decreased with increasing 25(OH)D only in major allele homozygotes (ß -0·02 (95 % CI -0·04, -0·01) mmol/l; ß -0·5 (95 % CI -0·9, -0·1) mmHg; and ß -0·5 (95 % CI -1·4, 0·3) pmol/l, respectively). In conclusion, genetic variation affected 25(OH)D substantially, but the genetic score was not associated with cardiometabolic markers in children. However, VDR polymorphisms modified associations with vitamin D, which warrants further investigation of VDR's role in the relationship between vitamin D and cardiometabolic risk.

Role of Vitamin D and Its Receptors in the Pathophysiology of Chronic Rhinosinusitis.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group. METHODS: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted. RESULTS: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data. CONCLUSIONS: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS.

Polymorphisms of Genes Related to Function and Metabolism of Vitamin D in Esophageal Adenocarcinoma.

PURPOSE: The vitamin D receptor (VDR) endocrine system has emerged as an endogenous pleiotropic biological cell regulator with anti-neoplastic effects on breast, colorectal, and prostatic adenocarcinomas. We studied the association of gene expression, polymorphisms of VDR, CYP27B1, and CYP24A1 genes and serum vitamin D levels as surrogate markers of disease progression in patients with acid reflux, Barrett's esophagus (BE), or esophageal adenocarcinoma (EAC). METHODS: We analyzed blood and tissue samples from patients with biopsy-confirmed BE or EAC for vitamin D levels, gene expressions, and polymorphisms in VDR (FokI [F/f], BsmI [B/b], ApaI [A/a], and TaqI [T/t]), CYP27B1 (HinfI [H/h]), and CYP24A1 (Hpy1881 [Y/y]). Percentages of homozygous dominant/recessive or heterozygous traits were assessed for each polymorphism in all patient subgroups. RESULTS: Genomic Bb and FF polymorphisms were highly prevalent in EAC patients, whereas BE patients had a high prevalence of wild-type Hpy1881 (YY polymorphism). Some polymorphisms (Yy for CYP24A1, bb for VDR) were noted only in EAC patients. Yy and bb forms were both uniquely present in some EAC patients without associated Barrett's lesions, but not in patients with concomitant BE. AA and bb polymorphisms were associated with decreased response to neoadjuvant therapy. A high level of VDR and CYP24A1 mRNA expression was observed in EAC tissue of non-responders. Serum vitamin D deficiency was common in EAC patients. CONCLUSIONS: Specific polymorphisms in vitamin D metabolism-related genes are associated with the likelihood of reflux-BE-EAC progression. Identifying such polymorphisms may aid in development of better surveillance and diagnostic and therapeutic protocols.

Normal physiological functions in two animal species with highly different vitamin d status compared to that of humans / Funciones fisiológicas normales en dos especies animales con estatus de vitamina d muy diferentes del actual en seres humanos

Mole rats live in permanent darkness, in networks of underground tunnels (which extend up to 1 km in the subsoil), excavated with their incisors, in warm and semi-arid areas of South Africa. Mole rats have an unusually impoverished vitamin D3 status with undetectable and low plasma concentrations of 25- hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3, respectively. They express 25-hydroxylase in the liver and 1-hydroxylase and 24-hydroxylase in their kidneys. The presence of specific receptors (VDR) was confirmed in the intestine, kidney, Harderʼs glands and skin. In spite of their poor vitamin D3 status, the apparent fractional intestinal absorption of calcium, magnesium and phosphate was high, always greater than 90%. Oral supplementation with cholecalciferol to mole rats did not improve the efficiency of gastrointestinal absorption of these minerals. Mole ratsdo not display the typical lesion of rickets: hypertrophic and radiolucent growth cartilages. Histological studies reported normal parameters of trabecular and cortical bone quality. Marmosets (monkeys of the New World) are not hypercalcaemic, eventhough they exhibit much higher levels of 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3 and parathyroid hormonethan that of rhesus monkeys and humans. Fed a high vitamin D3 intake (110 IU/day/100 g of body weight), a fraction of the experimental group was found to display osteomalacic changes in their bones: distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption. These findings suggest that some marmosets appears to suffer vitamin D-dependent rickets, type II. The maximum binding capacity of the VDR or the dissociation constant of VDR1α,25(OH)2D3 complex of mole rats and New World monkeys are distinctly different of VDR isolated from human cells. Health status of those species appears to be adaptations to the mutations of their VDR. Though rare, as mutations may occur at any time in any patient, the overall message of this review to clinicians may be: recent clinical studies strongly suggests that the normality of physiological functions might be a better indicator of the health status than the serum levels of vitamin D metabolites. (AU)

Las ratas topo viven en la oscuridad permanente, en redes de túneles subterráneos excavadas con sus incisivos (que se extienden hasta 1 km en el subsuelo), en áreas cálidas y semiáridas de Sudáfrica. Las ratas topo tienen un estatus de vitamina D3 inusualmente empobrecido con concentraciones plasmáticas indetectables de 25-hidroxivitamina D3 y bajas de 1α, 25-dihidroxivitamina D3. Poseen 25-hidroxilasa en el hígado y 1-hidroxilasa y 24-hidroxilasa en sus riñones. La presencia de receptores específicos (VDR) ha sido confirmada en el intestino, el riñón, las glándulas de Harder y la piel. A pesar de su pobre estatus de vitamina D3,la absorción fraccional intestinal aparente de calcio, magnesio y fosfato fue alta, siempre superior al 90%. La suplementación oral con colecalciferol a las ratas topo no mejoró la eficacia de la absorción gastrointestinal de estos minerales. No muestran la lesión típica del raquitismo: cartílagos de crecimiento hipertróficos y radiolúcidos. Varios estudios histológicos confirman los hallazgos radiológicos y se informan parámetros normales de la calidad ósea trabecular y cortical. Los titíes (monos del Nuevo Mundo) exhiben calcemias normales con niveles más elevados de 25-hidroxivitamina D3, 1α,25-dihidroxivitamina D3 y hormona paratiroidea que los monos rhesus y los seres humanos. Un tercio de un grupo de titíes alimentados con una alta ingesta de vitamina D3 (110 I/día/100 g de peso corporal) exhibió cambios osteomalácicos en sus huesos: aumento en la superficie osteoide, volumen osteoide y activa reabsorción osteoclástica. Estos hallazgos sugieren que una fracción de la población de titíes padece raquitismo dependiente de vitamina D, tipo II. Debido a mutaciones ocurridas hace millones de años, las máximas capacidades de ligamiento del VDR o los valores de la constante de disociación del complejo VDR-1α,25(OH)2D3 de las ratas topo o monos del Nuevo Mundo son muy diferentes de los verificables en receptores aislados de células humanas actuales. El mensaje de esta revisión a los médicos clínicos podría ser: varios estudios clínicos recientes indican que la normalidad de las funciones fisiológicas de un paciente es un mejor indicador de su salud que los niveles séricos de los metabolitos de la vitamina D. (AU)

Effects of two high dose vitamin-D by parenteral route in treating vitamin-D deficiency: a prospective interventional study.

Vitamin D deficiency is recognized as a global public health problem. Despite ample sunshine, vitamin D deficiency is very common in the Middle East (15°-36°N) and African (35°S-37°N) countries; and in South Asian countries. Different oral or parenteral dose modalities are tried for treatment of vitamin-D deficiency. Since the duration of corrective therapy is long; compliance of patients is a major issue. Herein we suggest a simple, affordable and practical plan to treat this very common deficiency.

The effects of vitamin D supplementation during pregnancy and maternal vitamin D levels on neonatal vitamin D levels and birth parameters.

OBJECTIVE: The current study aimed to measure the levels of vitamin 25(OH)D in pregnant women and in the umbilical cord blood of newborns and to evaluate the association of vitamin D levels with birth parameters. METHODS: This cross-sectional analytic investigation was performed in 100 pregnant women at term and in 100 newborns born to these mothers. Plasma vitamin D level was measured and birth parameters of the babies were recorded. RESULTS: Mean vitamin D levels in pregnant women and cord blood were 11.39 ± 6.24 ng/ml and 8.00 ± 4.95 ng/ml, respectively. Vitamin D levels were found to be higher in the women who had received vitamin D support during pregnancy (p < .001). Height (p = .004), head circumference (p = .003), and chest circumference (p = .005) of newborns born to mothers who had received vitamin D support were higher compared to non-receivers. Maternal vitamin D deficiency (<10 ng/ml) and insufficiency (10-30 ng/ml) was detected in 53.0% and 47.0% of the cases, respectively. None of the women had sufficient levels of vitamin D. CONCLUSIONS: This study established that vitamin D levels were low in maternal and cord blood in spite of the administration program of Ministry of Health in pregnant women. The importance of vitamin D supplementation should be explained to the pregnant women in each visit.

Cholecalciferol decreases inflammation and improves vitamin D regulatory enzymes in lymphocytes in the uremic environment: A randomized controlled pilot trial.

It has been reported that vitamin D regulates the immune system. However, whether vitamin D repletion modulates inflammatory responses in lymphocytes from dialysis patients is unclear. In the clinical trial, thirty-two (32) dialysis patients with 25 vitamin D ≤ 20ng/mL were randomized to receive either supplementation of cholecalciferol 100,000 UI/week/3 months (16 patients) or placebo (16 patients). In the in vitro study, B and T lymphocytes from 12 healthy volunteers (HV) were incubated with or without uremic serum in the presence or absence of 25 or 1,25 vitamin D. We evaluated the intracellular expression of IL-6, IFN-γ TLR7, TLR9, VDR, CYP27b1 and CYP24a1 by flow cytometry. We observed a reduction in the expression of TLR7, TLR9, INF-γ and CYP24a1 and an increase in VDR and CYP27b1 expression in patients which were supplemented with cholecalciferol, whereas no differences were found in the placebo group. Uremic serum increased the intracellular expression of IL-6, IFN-γ, TLR7, TLR9, VDR, CYP27b1 and CYP24a1. Treatment with 25 or 1,25 vitamin D decreased IL-6 and TLR9. CYP24a1 silencing plus treatment with 25 and/or 1,25 vitamin D had an additional reduction effect on IL-6, IFN-γ, TLR7 and TLR9 expression. This is the first study showing that cholecalciferol repletion has an anti-inflammatory effect and improves vitamin D intracellular regulatory enzymes on lymphocytes from dialysis patients.

Effect of cholecalciferol on vitamin D-regulatory proteins in monocytes and on inflammatory markers in dialysis patients: A randomized controlled trial.

BACKGROUND & AIMS: Hypovitaminosis D and inflammation are highly prevalent among patients undergoing dialysis, and the association of both conditions with worse survival has been well recognized. Although a potential role for vitamin D in the immune system has been suggested, the effect of the treatment of hypovitaminosis D on the modulation of the inflammatory response remains unclear. The aim of this study was to investigate the effect of the restoration of the vitamin D status on the expression of vitamin D-regulatory proteins in monocytes and on circulating inflammatory markers in dialysis patients. METHODS: In this randomized double-blind placebo-controlled 12-week trial, 38 patients on dialysis with serum 25-hydroxyvitamin D [25(OH)D] <20 ng/mL were randomized either to the cholecalciferol group (n = 20; 50,000 IU of cholecalciferol twice weekly) or to the control group (n = 18; 50 drops of a placebo solution twice weekly). The expression of vitamin D receptor (VDR), CYP27B1, CYP24A1 and interleukin-6 (IL-6) in monocytes was determined by flow cytometry. Serum concentrations of 25(OH)D, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were measured. The trial is registered at ClinicalTrials.gov #NCT01974245. RESULTS: After 12 weeks, the serum 25(OH)D increased from 14.3 ± 4.7 ng/mL to 43.1 ± 11.0 ng/mL (p < 0.05) in the cholecalciferol group and did not change in the control group (13.9 ± 4.2 ng/mL to 13.5 ± 4.3 ng/mL; p = 0.56). In monocytes, while CYP27B1 expression and VDR expression increased in the cholecalciferol group (p < 0.05), CYP27B1 expression did not change, and VDR expression decreased in the control group (p < 0.05). There were no changes in IL-6 and CYP24A1 expression in both groups. Serum concentration of IL-6 and CRP decreased from 8.1 ± 6.6 pg/mL to 4.6 ± 4.1 pg/mL (p < 0.05) and from 0.50 (0.10-1.27) mg/dL to 0.28 (0.09-0.62) mg/dL (p < 0.05), respectively only in the cholecalciferol group. Assessed overtime, the treatment group differences in 25(OH) D, PTH, CRP and IL-6, CYP27B1 and VDR remained significant. CONCLUSIONS: Restoration of vitamin D status of patients undergoing dialysis promoted upregulation of CYP27B1 and VDR expression in monocytes and a decrease in circulating inflammatory markers.

Decreased serum vitamin D levels in early spontaneous pregnancy loss.

BACKGROUND/OBJECTIVES: Effects of vitamin D deficiency in pregnancy have been associated with some adverse pregnancy outcomes. The objective of this study was to analyze the relationship between vitamin D deficiency in childbearing aged women and pregnancy loss (PL) in the first trimester. SUBJECTS/METHODS: This is a cross-sectional study. Plasma was collected from 60 nulliparous women with singleton at 7-9 weeks of gestation (30 with viable gestation and 30 with PL) and 60 non-gravid childbearing aged women (30 with a successful pregnancy history, and 30 with one or more spontaneous first-trimester PL history). Quantitation of serum 25-hydroxyvitamin D (25(OH)D) and 25-hydroxyvitamin D-1 alpha hydroxylase (CYP27B1) was assayed. RESULTS: By pregnancy/non-gravid, normal pregnant women had higher 25(OH)D (49.32 µg/l) and CYP27B1 (82.00 pg/ml) than PL women (34.49 µg/l and 37.87 pg/ml, both P<0.01); the non-gravid women with a successful pregnancy history also had higher 25(OH)D (39.56 µg/l) and CYP27B1 (39.04 pg/ml) than women with PL history (12.30 µg/l and 12.35 pg/ml, both P<0.01). The 96.7% of non-gravid women with PL history and 43.3% of PL women had serum 25(OH)D concentrations below 30 µg/l. There was a strong association between low vitamin D levels and PL (odds ratio 1.71; 95% confidence interval: 1.2-2.4, P<0.001). The regression analyses showed that PL was significantly inversely correlated with 25(OH)D (P<0.01) and CYP27B1 levels (P<0.01). CONCLUSIONS: Vitamin D deficiency associated with PL in the first trimester of pregnancy. Decreased serum vitamin D levels among childbearing aged women with the failed clinical pregnancies history may predispose to increased risk for PL.

No association between vitamin D and ß-cell autoimmunity in Finnish and Estonian children.

BACKGROUND: Vitamin D has immunomodulatory properties, such as regulation of FOXP3 expression and regulatory T-cell activity. Our aim was to investigate whether plasma 25-hydroxyvitamin D [25(OH)D] concentrations associate with the development of ß-cell autoimmunity and the transcriptional activity of FOXP3 or vitamin D3 convertase gene (CYP27B1) in CD4+ memory T cells. METHODS: We studied 83 Finnish and 32 Estonian children participating in the DIABIMMUNE and DIPP studies. Twenty-nine Finnish and six Estonian children tested positive for at least one diabetes-associated autoantibody. The plasma concentrations of 25(OH)D and 1,25(OH)2D were analysed with an enzyme immunoassay. Gene expression of FOXP3 and CYP27B1 in the isolated CD4+ memory T cells was studied with reverse transcription quantitative polymerase chain reaction. RESULTS: Vitamin D status did not differ between subjects positive and negative for ß-cell autoantibodies. Finnish children had higher vitamin D status than Estonian children (p < 0.001). FOXP3 expression was higher in Estonian CD4+ memory T-cell samples than in Finnish samples (p < 0.01) even when including in both groups only children with serum 25(OH)D concentrations in the range of 50-80 nmol/L (p < 0.001). CONCLUSIONS: These findings do not support a crucial role of circulating 25(OH)D as a regulator of ß-cell autoimmunity or FOXP3 expression.

[Two patients with renal medullary hyperechogenicity]. / Zwei Patientinnen mit echoreichen Markpyramiden.

HISTORY AND ADMISSION FINDINGS: We report two patients with medullary nephrocalcinosis and nephrolithiasis. The first patients had unspecific symptoms of a systemic inflammatory disease, the second patient was asymptomatic. INVESTIGATIONS: Both patients had normocalcemia and normal parathyroid hormone levels, very high 1,25(OH)(2)-vitamin D and normal to low 25-OH-vitamin D levels. On renal ultrasound, both patients displayed nephrocalcinosis and nephrolithiasis. DIAGNOSIS: Both patients showed dysregulation of the 1α-hydroxylase activity. The first patient suffered from a systemic inflammatory disease with consecutive activation of macrophages with extrarenal α-hydroxylase activity. The second patient had a "loss of function" mutation of the calcium sensing receptor with - for the situation - inadequatly high parathyroid hormone levels and consequently a renal dysregulation of the 1α-hydroxylase. TREATMENT AND COURSE: After immunosuppressive treatment with prednisolone and hydroxychloroquin there was complete remission of the systemic inflammatory disease in the first patient. In consequence the 1,25-(OH)(2)-vitamin D levels regressed and renal function stabilized. The second patient was completely asymptomatic with normal renal function, so far we did not initiate any treatment. CONCLUSIONS: Nephrocalcinosis and nephrolithiasis can result from hypercalciuria due to dysregulated hydroxylation of vitamin D. For both renal and extrarenal sources causal treatment is available.

Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids.

Considering that the vitamin D receptor as well as the 1-α-hydroxylase enzyme that converts 25-hydroxyvitamin D (25(OH)D) to its active form 1,25-dihydroxyvitamin D have been found in tissues throughout the body, it is likely that vitamin D is important for more than the calcium balance. Accordingly, low serum levels of 25(OH)D have been associated with mortality, cardiovascular disease, type 2 diabetes, hypertension and obesity. Low serum levels of 25(OH)D have also been associated with an unfavourable lipid profile, which could possible explain the relation with cardiovascular disease and mortality. However, the relation between vitamin D and lipids have so far received little attention and is therefore the main focus of the present review. A PubMed search identified 22 cross-sectional studies where serum levels of 25(OH)D and lipids were related and that included a minimum of 500 subjects, and 10 placebo-controlled double-blind intervention studies with vitamin D where more than 50 subjects were included. In all the cross-sectional studies serum 25(OH)D was positively associated with high-density lipoprotein cholesterol (HDL-C) resulting in a favourable low-density lipoprotein cholesterol (LDL-C) (or total cholesterol) to HDL-C ratio. There was also a uniform agreement between studies on a negative relation between serum 25(OH)D and triglycerides (TG). On the other hand, the intervention studies gave divergent results, with some showing a positive and some a negative effect of vitamin D supplementation. However, none of the intervention studies were specifically designed for evaluating the relation between vitamin D and lipids, none had hyperlipemia as an inclusion criterion, and none were sufficiently powered. In only one study was a significant effect seen with an 8% (0.28 mmol/L) increase in serum LDL-C and a 16% (0.22 mmol/L) decrease in serum TG in those given vitamin D as compared to the placebo group. Accordingly, the effect of vitamin D supplementation on serum lipids is at present uncertain. Considering the numerous other promising vitamins and minerals that when properly tested have been disappointing, one should wait for the results of forthcoming vitamin D intervention studies before drawing conclusions on potential beneficial effects of vitamin D.

A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations.

In order to appreciate the association between hypovitaminosis D and various adverse health outcomes, we require a thorough understanding of how common single nucleotide polymorphisms (SNPs) influence serum concentrations of 25-hydroxyvitamin D (25OHD). We undertook a systematic review of the literature in order to identify studies that examined 25OHD concentrations, and common SNPs. We found nine studies related to the vitamin D binding protein (group-specific component, GC), and five studies examining the vitamin D receptor (VDR). SNPs in a range of cytochrome P450 enzymes have also been examined in seven studies. Replicated findings have been found between 25OHD concentrations and (a) two SNPs in GC (rs4588, rs7041), (b) one SNP in VDR (rs10735810), and (c) one SNP in CYP27B1 (rs10877012). In light of these associations, it is feasible that optimal concentrations of 25OHD required to reduce disease outcomes may vary according to genotype. We speculate that recently identified U-shaped relationships between 25OHD concentrations and disease outcomes (i.e. increased risk at both high and low concentrations) may reflect a mixture of genotype-defined subgroups. Further research is required in order to clarify the genetic architecture underlying 25OHD serum concentrations, and to unravel the mechanisms of action responsible for these associations.

Deficiencia de vitamina D y su relación con la fractura de cadera del anciano y la densidad mineral ósea de la mujer posmenopáusica / Vitamin D deficiency and its relationship with hip fracture of the elderly and bone mineral density of the postmenopausal woman

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Increased expression of the 25-hydroxyvitamin D(3)-1alpha-hydroxylase gene in alveolar macrophages of patients with lung cancer.

25-Hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase) plays a central role in calcium metabolism by synthesizing the active hormone 1alpha,25-dihydroxyvitamin D(3) in the kidney. Its increased expression in the extrarenal tissues has been found in alveolar macrophages in sarcoidosis but not in any other pathological conditions. We found that 1alpha-hydroxylase-mRNA in alveolar macrophages measured by semiquantitative RT-PCR was 2-fold greater in patients with lung cancer than in control subjects (0.61 +/- 0.20 vs. 0.34 +/- 0.11, respectively; P < 0.0001). When the clinical stages of lung cancer were divided into early (stage IA-IIIA) and advanced (stage IIIB and IV) and the expression of 1alpha-hydroxylase gene was compared among the control, early, and advanced groups, the advanced group showed the highest expression, followed by the early group, then the control group (0.34 +/- 0.11, 0.52 +/- 0.11, and 0.69 +/- 0.23 for control, early, and advanced groups, respectively; P < 0.0001). The 1alpha-hydroxylase-mRNA level was well correlated with serum 1alpha,25-dihydroxylase D(3) concentration and the 1alpha,25-dihydroxylase D(3) to 25-hydroxyvitamin D(3) ratio, but none of the findings related to calcium metabolism among the patients with lung cancer. Increased local production of 1alpha,25-dihydroxyvitamin D(3) may be associated with the pathological conditions, such as immunosuppression, in lung cancer.

PTH increases renal 25(OH)D3-1alpha -hydroxylase (CYP1alpha) mRNA but not renal 1,25(OH)2D3 production in adult rats.

The capacity of parathyroid hormone (PTH) to stimulate renal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production declines with age in the rat. The purpose of these studies was to determine whether this decline is due to a decreased capacity of PTH to increase the mRNA levels of CYP1alpha, the cytochrome P-450 component of the 25(OH)D(3)-1alpha-hydroxylase. Young (2 mo) and adult (12 mo) male Fischer 344 rats were parathyroidectomized (PTX). After 72 h, PTX rats were injected with PTH or vehicle at 24, 6, and 3 h before death, and renal CYP1alpha mRNA levels were measured by ribonuclease protection assay. In young rats, PTH markedly increased plasma 1,25(OH)(2)D(3) and renal 1,25(OH)(2)D(3) production. However, in adult rats, the response to PTH was less than 30% of that seen in young rats. Renal CYP1alpha mRNA levels, on the other hand, were increased over fivefold by PTH in both young and adult rats. In in vitro studies, PTH/forskolin increased CYP1alpha mRNA levels over twofold in renal slices from both young and adult PTX rats. These studies demonstrate that the decreased capacity of PTH to increase 1,25(OH)(2)D(3) production in adult rats is not due to decreased induction of CYP1alpha mRNA.