Modulation Of Vitamin Research Articles

Dietary Sources, Sex, and rs5888 (SCARB1) as Modulators of Vitamin A's Effect on Cardiometabolic Health.

Although preclinical studies have attributed vitamin A (VA) cardiometabolic benefits, these effects are still controversial and not always supported in large human studies. Here, the outcomes associated with VA and its relationship with habitual dietary sources, sex, and genetic background have been studied. To do so, the data from an observational study (n = 455) (64% females, mean age of 36 years) showing that suboptimal VA intake (mainly from retinol rather than carotene) is associated with cardiometabolic risk (CMR) were considered. A higher odds ratio (OR) of suffering ≥ 2 simultaneous CMR factors was observed in men in the low consumption tercile of retinol (OR = 2.04; p = 0.019). In women, however, this relationship was not evident. Then, incubation of peripheral blood mononuclear cells (PBMCs) with VA-related compounds (ex vivo functional assay from 81 men and women) induced specific changes in the activity of genes involved in lipid homeostasis and inflammatory status, which were dependent on the type of compound tested and the sex of the person. In addition, the presence of the genetic variant rs5888 in SCARB1 was identified as having a high influence on VA-related metabolic response. The new evidence derived from this study could be relevant for personalized nutritional advice concerning VA and CMR.

GC1f Vitamin D Binding Protein Isoform as a Marker of Severity in Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are characterized by a wide spectrum of clinical, behavioral, and cognitive manifestations. It is, therefore, crucial to investigate possible biomarkers associated with specific ASD phenotypes. Ample literature suggests a possible role for vitamin D (VD) in influencing ASD clinical phenotypes. We analyzed three vitamin D binding protein gene (DBP) functional polymorphisms (rs2282679, rs7041, and rs4588), which are involved in the modulation of vitamin D serum concentration in 309 ASD children and 831 healthy controls. Frequency comparisons of single nucleotide polymorphisms (SNPs) alleles, genotypes, and GC isoforms (GC1f, G1s, and GC2)—generated by the combination of rs7041 and rs4588 alleles—were correlated with ASD diagnostic, behavioral, and functioning scales. The GC1f isoform was significantly more frequent in ASD compared with controls (18.6% vs. 14.5% pc = 0.02). Significantly higher scores for item 15 of the Childhood Autism Rating Scale (CARS) and lower ones for the Children’s Global Assessment Scale (CGAS) functioning scales were seen in ASD carrying the GC1f isoform. In GC phenotype analysis, a gradient of severity for overall CARS scores and CARS item 15 was observed, with scores decreasing according to the presence of GC1f-GC1f > GC1f-GC1s > GC1s-GC1s > GC1f-GC2 > GC2-GC2 isoforms. Similarly, lower CGAS scores were seen in carriers of the GC1f-GC1f isoform, whereas higher scores were present in those carrying GC2-GC2 (p = 0.028). This is the first study to evaluate possible relationships between GC variants and the different aspects of ASD in Italian ASD children. Results, although needing to be validated in ampler cohorts, suggest that the GC1f isoform could be a marker of severity in ASD that may be useful in establishing the intensity of therapeutic and rehabilitative protocols.

Effect of Application of Different Exercise Intensities on Vitamin D and Parathormone in Children with Down's Syndrome.

Background Children with Down's syndrome are more liable to vitamin D deficiency. Treating this deficiency with supplements is associated with the risk of intoxication. Aim The study is aimed at comparing the effect of two exercise intensities on the modulation of vitamin D and parathormone levels in children with DS. Methods Forty-four DS male children aged from 8 to 12 years participated in the study. They were assigned randomly into two equal groups. Group I received high-intensity treadmill aerobic exercises, and group II received moderate-intensity T-AE, three times per week for three months. The blood samples were collected from both groups before the intervention, after one month of intervention, then after three months of intervention to assess serum 25(OH)D and PTH levels. Results Repeated measure MANOVA revealed that the high-intensity T-AE induced a significant increase in 25(OH)D after one month and after three months while it significantly decreased PTH only after three months. Moderate-intensity T-AE had a nonsignificant effect on both hormones. Conclusion The current study concluded that the high-intensity T-AE improved both vitamin D and parathormone serum levels after three months of intervention.

The threshold between life and death in Cistus albidus L. seedlings: mechanisms underlying drought tolerance and resilience.

Drought can lead to important shifts in population dynamics if it occurs during seedling establishment. With the aim of elucidating the underlying mechanisms of drought tolerance and resilience, here we monitored the survival of seedlings of the Mediterranean shrub Cistus albidus L. throughout a year growing in the natural Park of the Montserrat Mountains (Spain) and, additionally, we studied the response to severe drought and subsequent recovery after rewatering of seedlings grown in growth chambers. To find possible mechanisms explaining how seedlings respond to drought, growth and survival together with physiological-related parameters such as chlorophyll contents, vitamin E and stress-related phytohormones were measured. We found that survival decreased by 30% at the end of summer and that the main proxy of seedling survival was total chlorophyll. This proxy was further confirmed in the growth chambers, where we found that seedlings that recovered from drought had higher levels of total chlorophyll compared with the seedlings that did not recover. Furthermore, modulation of vitamin E and jasmonates contents appeared to be crucial in the drought response of C. albidus seedlings. We propose a prediction model of survival that includes total chlorophyll height, leaf mass area and maximum photosystem II efficiency with chlorophyll contents being a good long-term predictor of C. albidus seedling survival under severe stress, which, in turn, could help to better foresee population fluctuations in the field.

P431 Vitamin D binding protein in the limelight: IBD-related inflammation and circulating levels of vitamin D binding protein, total, free and bioavailable 25-hydroxyvitamin D

Abstract Background Vitamin D deficiency occurs frequently in patients with Crohn’s disease (CD) and ulcerative colitis (UC). While recent cohort studies support an association of vitamin D with important clinical parameters and outcomes in IBD, the complex interplay of inflammation with vitamin D metabolism in IBD poses a viscious circle. We sought to further illucidate the relation between inflammation and different vitamin D parameters. To the best our knowledge, this was the first study to focus on the relationship between vitamin D binding protein (VDBP), circulating total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D), and inflammation, in adult IBD patients. Methods This was a comparative, single-centred, cross-sectional study in patients with IBD aged 18–65 years. Full blood count, transferrin, albumin and hsCRP were determined by standard methods. The presence/absence of inflammation was assessed based on serum hsCRP levels (cutoff <5mg/l). VDBP levels were determined by ELISA, and 25(OH)D by LCMS. Free and bioavailable vitamin D levels were calculated using the validated formula. IBM SPSS version 25.0 was used for statistical analysis. Results In total, 129 subjects with IBD (70 male/59 female; 82 CD/47 UC; mean age 41.7 ± 12.6 years) were enrolled. Of these, 38/129 had inflammation (19 m/19 f; 26 CD/12 UC; 39.6 ± 12.9 years) while 91/129 had no inflammation (40 m/51 f; 56 CD/35 UC; 42.5 ± 12.5 years). Subjects with disease activity had significantly higher leukocyte, erythrocyte sedimentation rate (ESR) and hsCRP, but lower transferrin, transferrin saturation (TSAT) and albumin levels than those without inflammation (p < 0.05). Average serum levels of 25(OH)D (24.6[6.8–54.8] vs. 26.4[5.0–74.4]ng/ml), free 25(OH)D (5.9[1.3–13.3] vs. 1.0[1.0–21.4]ng/ml) and bioavailable 25(OH)D(2.3 [0.1–4.7] vs. 2.4[0.5–19.5]ng/ml) were similar in patients with vs. without inflammation (p > 0.05). However, VDBP levels were significantly higher in inflammatory conditions (359.6[252.2–530.6] mg/l vs. 327.4[183.5–560.3]mg/l; p < 0.05) and showed a positive correlation with CRP levels (0.293, p < 0.001). Ratio of free/total 25(OH)D correlated negatively with CRP levels (−0.282, p = 0.002). Conclusion High levels of circulating VDBP were associated with inflammatory activity. Moreover, free/total 25(OH)D ratio was inversely associated with inflammation. Other vitamin D parameters including total, free and bioavailable 25(OH)D showed no association with inflammation. These findings suggest that VDBP may play a bigger role than thought as a modulator of vitamin D and inflammation, and that simultaneous detection and investigation of plasma VDBP may provide additional insights into this complex interaction.

Modulation of vitamin D signaling by the pioneer factor CEBPA

The myeloid master regulator CCAAT enhancer-binding protein alpha (CEBPA) is known as a pioneer factor. In this study, we report the CEBPA cistrome of THP-1 human monocytes after stimulation with the vitamin D receptor (VDR) ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) for 2, 8 and 24 h. About a third of the genomic VDR binding sites co-located with those of CEBPA. In parallel, the binding strength of 5% of the CEBPA cistrome, i.e. some 1500 sites, is significantly (p < 0.001) affected by 1,25(OH)2D3. Transcriptome-wide analysis after CEBPA silencing indicated that the pioneer factor enhances both the basal expression and ligand inducibility of 70 vitamin D target genes largely involved in lipid signaling and metabolism. In contrast, CEBPA suppresses 82 vitamin D target genes many of which are related to the modulation of T cell activity by monocytes. The inducibility of the promoter-specific histone marker H3K4me3 distinguishes the former class of genes from the latter. Moreover, prominent occupancy of the myeloid pioneer factor PU.1 on 1,25(OH)2D3-sensitive CEBPA enhancers mechanistically explains the dichotomy of vitamin D target genes. In conclusion, CEBPA supports vitamin D signaling concerning actions of the innate immune system, but uses the antagonism with PU.1 for suppressing possible overreactions of adaptive immunity.

The mechanism of statin-induced modulation of vitamin D metabolism

The mechanism of statin-induced modulation of vitamin D metabolism

Effect of exercise on serum vitamin D and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus

This work aimed to study the effect of swimming exercise on serum vitamin D level and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus. Sixty adult male rats were divided into control and diabetic groups. Each was further subdivided into sedentary and exercised subgroups. Diabetes Mellitus was induced by a single intraperitoneal dose of streptozotocin (50mg/kg) dissolved in cold 0.01M citrate buffer (pH 4.5). The exercised subgroups underwent swimming for 60min, 5 times a week for 4weeks. Serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipids, vitamin D and tissue Vitamin D receptors (VDR) were evaluated. Significant increase in serum glucose, insulin, HOMA-IR, cholesterol, triglycerides, and low density lipoprotein (LDL) levels in sedentary diabetic rats was detected. On the other hand, high density lipoprotein (HDL), free fatty acids, serum vitamin D and pancreatic, adipose, and muscular VDR showed a significant decrease in the same group. It is evident that all these parameters were reversed by swimming exercise indicating its beneficial role in type 2 Diabetes. In diabetic groups; serum vitamin D was found to be correlated negatively with serum glucose, insulin, HOMA, cholesterol, triglycerides, and LDL and positively correlated with HDL and tissue VDR. In conclusion, Disturbed vitamin D is associated with metabolic impairments in sedentary diabetic rats. Moderate swimming exercise is beneficial in improving these consequences through modulation of vitamin D status. Future studies could be designed to investigate the effect of the combination of vitamin D intake with exercise in diabetic patients.

Vitamin D Receptor Polymorphisms Relate to Risk of Adenomatous Polyps in a Sex-Specific Manner

ABSTRACTVitamin D receptor (VDR) gene polymorphisms may influence risk for adenomatous polyps (AP), a benign precursor to colon cancer, via modulation of vitamin D sensitive pathways, including cell proliferation and differentiation. However, results have been mixed and any association remains contentious. Failure to clinically exclude the presence of (AP in control cohorts may contribute to the lack of consensus. Therefore, we assessed the role of the FokI, BsmI, ApaI, and TaqI VDR polymorphisms in modifying risk for AP, adjusting for a range of dietary and lifestyle variables. Blood was collected from colonoscopy patients (n = 258) and VDR polymorphisms assessed by restriction fragment length polymorphism. Dietary habits were estimated from food frequency questionnaires. Odds ratios for AP were calculated by genotype, stratified by sex, and adjusted for age, lifestyle, and dietary factors. FokI was associated with modified risk for AP in males, whereas the BsmI/ApaI/TaqI haplotype was associated with modified risk in females. No interaction was found between VDR variants and vitamin D intake. This study offers novel insight into the potential for VDR genetics to contribute to risk for AP and is the first to demonstrate a sex-specific relationship between these polymorphisms and risk for AP.

Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.

The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.

Treatment of Multiple Sclerosis – Relationship between Vitamin D and Interferon β-1b

There are many reports suggesting an association between vitamin D status and both the development of multiple sclerosis (MS) and its course. This relationship and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of patients are reviewed in the BEtaferon/ Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. In the BENEFIT study the average serum 25-hydroxyvitamin D (25[OH]D) levels strongly predicted MS disease activity and progression. The probability of clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity was lower in these clinically isolated syndrome (CIS) patients with 25(OH)D levels ≥50 nmol/L and in those starting with IFNβ -1b. Furthermore, there was a beneficial effect on relapse rate, occurrence of new active MRI lesions and disease progression for a 50 nmol/L increase in 25(OH)D levels. Similarly, in relapsing-remitting (RR) MS patients from the BEYOND study serum 25(OH)D levels were inversely associated with MRI markers of MS activity. Genetic analysis of patients from these studies indicated that there may be a benefit in monitoring and managing vitamin D levels in early MS patients treated with IFNβ-1b and a cumulative number of risk alleles predict lower 25(OH)D levels in CIS and RRMS patients. Further studies have suggested that some of the IFNβ-1b therapeutic effects on relapse could be mediated through modulation of vitamin D metabolism. Thus, there seems to be a benefit on clinical and MRI measures if patients are treated with both vitamin D and IFNβ-1b. There is a need to further evaluate this effect in clinical trials. The relationship between vitamin D and MS disease activity along with the effects of vitamin D and IFNβ-1b in the treatment of MS patients is reviewed.

Modulators of vitamin D nuclear receptor: recent advances from structural studies.

The vitamin D nuclear receptor (VDR) and its ligand, 1α, 25-dihydroxyvitamin D3 (1,25(OH)2D3, or calcitriol) regulate numerous biological functions. Therefore, VDR represents an important therapeutic target in the treatment of various diseases such as cancers, psoriasis, rickets, renal osteodystrophy, and autoimmune dysfunctions. Despite the number of newly synthesized 1,25(OH)2D3 analogues, the need for highly potential modulators of VDR with precise cell-, gene- or coregulator-selectivity still exists. The information coming from the analysis of crystal structures of VDR-ligand complexes remains one of the most powerful tools to explain and validate the properties of the compounds and, furthermore, to gain new rationales for their modification. The number of reports on VDR-ligand recognition is constantly rising, and herein we review the recently published structural data. With the emphasis on the most promising compounds, such as secosteroidal compounds and 1,25(OH)2D3 mimics, we also highlight other natural ligands for VDR, evidence for the existence of an alternative ligand binding site within LBP, and identification of novel VDR modulators.

Modulation of Vitamin D Status and Dietary Calcium Affects Bone Mineral Density and Mineral Metabolism in Göttingen Minipigs

Calcium and vitamin D deficiency impairs bone health and may cause rickets in children and osteomalacia in adults. Large animal models are useful to study experimental osteopathies and associated metabolic changes. We intended to modulate vitamin D status and induce nutritional osteomalacia in minipigs. The control group (n = 9) was fed a semisynthetic reference diet with 6 g calcium and 6,500 IU vitamin D3/kg and the experimental group (n = 10) the same diet but with only 2 g calcium/kg and without vitamin D. After 15 months, the deficient animals were in negative calcium balance, having lost bone mineral density significantly (means ± SEM) with −51.2 ± 14.7 mg/cm3 in contrast to controls (−2.3 ± 11.8 mg/cm3), whose calcium balance remained positive. Their osteoid surface was significantly higher, typical of osteomalacia. Their plasma 25(OH)D dropped significantly from 60.1 ± 11.4 nmol/L to 15.3 ± 3.4 nmol/L within 10 months, whereas that of the control group on the reference diet rose. Urinary phosphorus excretion and plasma 1,25-dihydroxyvitamin D concentrations were significantly higher and final plasma calcium significantly lower than in controls. We conclude that the minipig is a promising large animal model to induce nutritional osteomalacia and to study the time course of hypovitaminosis D and associated functional effects.

Abstract B32: Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells

Abstract Vitamin D has been proposed as a chemopreventive agent for colorectal cancer; however, the mechanisms governing the availability of the active form of vitamin D, 1α,25(OH)2D, remain unclear. There is growing evidence that uptake of vitamin D metabolites at the cellular level may involve receptor-mediated endocytosis in certain tissues. Megalin, or low-density lipoprotein 2, has demonstrated effects on uptake of Gc-globulin (GC)-bound vitamin D metabolites in kidney, bone, gallbladder, and mammary gland cells. However, this mode of metabolite uptake has not been tested in the colon. We measured activation of the VDR-RXR heterodimer in the context of a mammalian-2-hybrid (M2H) biological assay system as a marker for uptake of vitamin D metabolites in human HCT-116 colorectal carcinoma cells. Cells were transfected with control versus megalin siRNA or, alternatively, no siRNA but treatment with receptor associated protein (RAP), a ligand for megalin that blocks GC binding. Cells were then treated with ethanol (EtOH) vehicle versus 1x10-8 M, 2.5x10-9 M, or 5x10-10 M 1α,25(OH)2D. The results demonstrate that treatment with either megalin siRNA or RAP induced an overall statistically significant increase in activation of the VDR-RXR heterodimer (ANOVA p&amp;lt; 0.001) compared to control siRNA, after controlling for differences by replicate and 1α,25(OH)2D concentration. Furthermore, stratification by concentration and use of the Tukey HSD test for pairwise comparisons revealed that activation following treatment with megalin siRNA was greater than with RAP, but not statistically significantly different. Activation with megalin siRNA was significantly different from control siRNA at all three 1α,25(OH)2D concentrations compared to EtOH (p&amp;lt; 0.05); however, treatment with RAP only led to the significant increase at 1x10-8 M 1α,25(OH)2D. Further work is ongoing to test uptake of 25(OH)D and an additional assay based upon vitamin D response element binding. These results provide preliminary evidence that colon cells use megalin to regulate uptake of 1α,25(OH)2D and that its presence acts to limit uptake, especially when extracellular concentrations of 1α,25(OH)2D are high. These results identify megalin as a novel target and modulator of vitamin D metabolite delivery at the cellular level that may influence population-level cancer risk. Additional testing of these results under varied cell conditions and in multiple cell lines is necessary to further elucidate the role of megalin in uptake of vitamin D metabolites into cancer cells. Citation Format: Elizabeth A. Hibler, Elizabeth T. Jacobs, Peter W. Jurutka. Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B32.

Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS

To determine whether interferon-β (IFN-β) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk. In a prospective cohort of 178 persons with clinically definite multiple sclerosis (MS) living in southern Tasmania in 2002-2005, serum 25-hydroxyvitamin D [25(OH)D] was measured biannually, with assessment by questionnaire for relevant factors, including IFN-β treatment. Subjects reporting IFN-β use had significantly higher mean 25(OH)D than persons who did not (p < 0.001). This was mediated by an interaction between personal sun exposure and IFN-β, with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy. The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-β therapy (p = 0.82). 25(OH)D was associated with a reduced relapse risk only among persons on IFN-β (p < 0.001). Importantly, IFN-β was only protective against relapse among persons with higher 25(OH)D (hazard ratio [HR] 0.58 [95% confidence interval (CI) 0.35-0.98]), while among 25(OH)D-insufficient persons, IFN-β increased relapse risk (HR 2.01 [95% CI 1.22-3.32]). In this study, we found that IFN-β therapy is associated with greater production of vitamin D from sun exposure, suggesting part of the therapeutic effects of IFN-β on relapse in MS may be through modulation of vitamin D metabolism. These findings suggest persons being treated with IFN-β should have vitamin D status monitored and maintained in the sufficiency range. This study provided Class III evidence that IFN-β is associated with reduced risk of relapse, and this effect may be modified by a positive effect of IFN-β on serum 25(OH)D levels.

APOEε4is associated with higher vitamin D levels in targeted replacement mice and humans

The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE ε4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.

Modulation of vitamin D signaling is a potential therapeutic target to lower cardiovascular risk in chronic kidney disease

SummaryWhile it is true that many traditional cardiovascular risk factors are amenable to intervention in chronic kidney disease (CKD), the results of intervention may not be as efficacious as those obtained in the general population. Thus, there may also be a unique milieu established in CKD, which causes excess cardiovascular disease (CVD) burden by mechanisms that are as yet not fully recognized. Recently, vitamin D has sparked widespread interest because of its potential favorable benefits on CVD. However, the mechanisms for how vitamin D may improve CVD risk markers and outcomes have not been fully elucidated. Furthermore, hypovitaminosis D is highly prevalent in the CKD cohort. Given this background, we hypothesize that low vitamin D status may act as a new CVD risk marker, and modulation of vitamin D signaling may be a potential therapeutic target to lower cardiovascular risk in CKD. The data presented in this review support that the low vitamin D status may be linked with the high cardiovascular risk in CKD, based on both the biological effects of vitamin D itself on the cardiovascular system, and the cross-actions between vitamin D signaling and the multiple metabolic pathways. Considering the high prevalence of hypovitaminosis D, limited natural vitamin D food sources, and reduced sun exposure in CKD patients, recommendations for treatment of hypovitaminosis D mainly focus on exogenous supplementation with vitamin D and its analogues. Although promising, when to start therapy, the route of administration, the dose, and the duration remain need to be discussed.

Abstract 2798: VDR gene polymorphism and risk of prostate cancer in African-American

Abstract Background: Genetics and epidemiological studies have shown that genes and environment interaction play strong roles in prostate cancer etiology. We have already shown that higher UV exposure, higher serum vitamin D, and lower skin pigmentation inversely associated with the risk of prostate cancer in African-American. Methods: In order to explore the relationship between Vitamin D receptor (VDR) polymorphisms and prostate cancer risk in African American men; 91 affected African American men with histologically diagnosed adenocarcinoma of the prostate, PSA of &amp;gt; 2.5 ng/ml and a positive digital rectal exam have been recruited. Ninety-one age and ethnicity matched controls have been also recruited. Genomic DNA was extracted from blood sample of each case and control subjects. Nine primers were designed for amplification of 9 different axons in VDR gene. DNA fragments from all samples were amplified using PCR reaction. In order to investigate the existence of heteroduplex, PCR products denatured and using denaturing high performance liquid chromatography (DHPLC) technique heteroduplex analysis on the Wave system was performed. Those samples demonstrating heteroduplex peaks were sequenced using an ABI 377 DNA sequencer. Results: Seven polymorphisms in VDR sequence were confirmed after sequencing. SNPs 132G&amp;gt;A, 332 G&amp;gt;A, 83 G&amp;gt;A, invs9-286C&amp;gt;T, 122 A&amp;gt;G, and invs10-49G&amp;gt;T are located in non-coding region. 209 T&amp;gt;C SNP is located in coding region. However this SNP is anonymous as previously reported. 332G&amp;gt;A, 83G&amp;gt;A, and invs9-286C&amp;gt;T SNPs showed strong negative association with prostate cancer risk (p&amp;lt; 0.05). 132G&amp;gt;A, 209T/C, and IVS10-49G&amp;gt;T showed direct association with risk of prostate cancer but statistically is not significant. Using Binary Logistic Regression Model confirmed that 332G&amp;gt;A, 83G&amp;gt;A, and invs9-286C&amp;gt;T SNPs are good predictor of protection against prostate cancer. Whereas having SNP 209T&amp;gt;C is strong indicator of risk of prostate cancer. Conclusion: It is possible that genetic variants may mediate prostate cancer risk via a mechanism involving availability of 1, 25(OH)2 D. Vitamin D protects against risk of prostate cancer. UV exposure, good vitamin D diet, and lighter skin along with advantageous VDR polymorphism as modulators of vitamin D can improve this protection. We are in the process of assessment of analysis the interaction between other genes involved in vitamin D metabolism and environmental factors. Our results require further corroboration in large statistically powerful sample collections. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2798.

Modulation of Vitamin D Receptor Activity by the Corepressor Hairless: Differential Effects of Hairless Isoforms

The vitamin D receptor (VDR) and its corepressor Hairless (HR) are thought to regulate key steps in the hair cycle because mutations in VDR or HR cause alopecia in humans and mice. Many mammalian cells express two major HR isoforms due to alternative splicing of exon 17. HR isoform-a encodes an 1189-amino acid protein (full-length HR), and isoform-b encodes an 1134-amino acid protein (HRDelta1072-1126). We demonstrated that both HR isoforms are expressed in primary human keratinocytes and in the human keratinocyte cell line HaCaT. In transfected COS-7 cells, the full-length HR repressed VDR-mediated transactivation. In contrast, HRDelta1072-1126 failed to suppress and even stimulated VDR-mediated transactivation. In coimmunoprecipitation, both HR isoforms interacted with the VDR, but only the full-length HR interacted with histone deacetylase 1 (HDAC1). Alanine mutagenesis of two conserved glutamic acids residues (E1100A/E1101A) encoded by exon 17 completely eliminated HR corepressor activity and interactions with HDAC1. When the two HR isoforms were coexpressed in COS-7 cells, the corepressor activity of the full-length HR was not antagonized by the HRDelta1072-1126 isoform. When transfected into HaCaT cells, the full-length HR inhibited endogenous CYP24A1 basal gene expression as well as 1,25-dihydroxyvitamin D3-stimulated CYP24A1 expression. HRDelta1072-1126 failed to suppress basal or 1,25-dihydroxyvitamin D3-stimulated CYP24A1 gene expression. In conclusion, we have demonstrated that both HR isoforms are expressed in keratinocytes and that the HRDelta1072-1126 isoform lacks corepressor activity and is unable to bind HDACs. HRDelta1072-1126 may function as a coactivator in some settings by inhibiting HDAC recruitment to the VDR transcriptional complex.

Vitamin D Status Is Positively Correlated with Regulatory T Cell Function in Patients with Multiple Sclerosis

BackgroundIn several autoimmune diseases, including multiple sclerosis (MS), a compromised regulatory T cell (Treg) function is believed to be critically involved in the disease process. In vitro, the biologically active metabolite of vitamin D has been shown to promote Treg development. A poor vitamin D status has been linked with MS incidence and MS disease activity. In the present study, we assess a potential in vivo correlation between vitamin D status and Treg function in relapsing remitting MS (RRMS) patients.Methodology/Principal FindingsSerum levels of 25-hydroxyvitamin D (25(OH)D) were measured in 29 RRMS patients. The number of circulating Tregs was assessed by flow-cytometry, and their functionality was tested in vitro in a CFSE-based proliferation suppression assay. Additionally, the intracellular cytokine profile of T helper cells was determined directly ex-vivo by flow-cytometry. Serum levels of 25(OH)D correlated positively with the ability of Tregs to suppress T cell proliferation (R = 0.590, P = 0.002). No correlation between 25(OH)D levels and the number of Tregs was found. The IFN-γ/IL-4 ratio (Th1/Th2-balance) was more directed towards IL-4 in patients with favourable 25(OH)D levels (R = −0.435, P = 0.023).Conclusions/SignificanceThese results show an association of high 25(OH)D levels with an improved Treg function, and with skewing of the Th1/Th2 balance towards Th2. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in MS patients. It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases. Future intervention studies will show whether modulation of vitamin D status results in modulation of the T cell response and subsequent amelioration of disease activity.