scholarly journals The CYP24A1 Gene Variant rs2762943 Is Associated With Low Serum 1,25- Dihydroxyvitamin D Levels In Multiple Sclerosis Patients

2021 ◽  
Author(s):  
Sunny Malhotra ◽  
Luciana Midaglia ◽  
Omar Chuquisana ◽  
Nikolaos A Patsopoulos ◽  
Roser Ferrer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Risk Allele ◽  
Active Form ◽  
Gene Variant ◽  
Gm Csf ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Increased Risk ◽  
Multiple Sclerosis Patients

Abstract Background: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. We recently identified a polymorphism located in the cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene, rs2762943, that was found to be associated with an increased risk for MS. CYP24A1 codes for a protein that is involved in the catabolism of the active form of vitamin D. Here, we investigated the immunological effects of carrying the risk allele for the rs2762943 polymorphism, as well as its role as genetic modifier in MS patients. Methods: Serum levels of 25‐hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in a cohort of 167 MS patients. In a subgroup of these patients, expression levels of MHC class II and co-stimulatory molecules were determined by flow cytometry in blood cell populations, and the levels of proinflammatory (IFNG, GM-CSF, CXCL13) and anti-inflammatory (IL-10) cytokines and neurofilament light chain were measured by single-molecule array assays in serum samples. The effect of the rs2762943 polymorphism on disease activity and disability progression measures was evaluated in a cohort of 340 MS patients. Results: Compared to non-carriers, MS patients carrying the risk allele for rs2762943 were characterized by reduced levels of 1,25(OH)2D (p=0.0001), and elevated levels of IFNG (p=0.03) and GM-CSF (p=0.008), whereas no significant differences were observed between risk allele carriers and non-carriers groups for the other evaluated markers. The presence of the risk allele for rs2762943 had no significant impact on the annualized relapse rate, EDSS and MSSS measures during follow-up. However, risk allele carriers were younger at disease onset (p=0.04). Discussion: These findings suggest that the CYP24A1 rs2762943 gene variant plays a more important role on MS susceptibility than on disease prognosis, and is associated with lower 1,25(OH)2D levels and heightened pro-inflammatory environment in MS patients.

Assessment of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D3 concentrations in male and female multiple sclerosis patients and control volunteers

2007 ◽  
Vol 13 (5) ◽  
pp. 670-672 ◽  
Author(s):  
M.S. Barnes ◽  
M.P. Bonham ◽  
P.J. Robson ◽  
J.J. Strain ◽  
A.S. Lowe-Strong ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Active Form ◽  
Plasma Concentrations ◽  
Secondary Analysis ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Multiple Sclerosis Patients ◽  
And Control

Populations with insufficient ultraviolet exposure and who consume diets low in vitamin D have low vitamin D status (plasma 25-hydroxyvitamin D (25(OH)D) concentrations) and a reported higher incidence of multiple sclerosis (MS). The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an effective anti-inflammatory molecule. No research to date has assessed 1,25(OH)2D3 concentrations in individuals with MS. In this study, plasma concentrations of 25(OH)D, 1,25(OH)2D 3 and parathyroid hormone (PTH) were measured in 29 individuals with MS and 22 age- and sex-matched control volunteers. There were no significant differences in plasma PTH, 25(OH)D and 1,25(OH)2D3 concentrations between individuals with MS and control volunteers. Women with MS had significantly higher 25(OH)D and 1,25(OH)2D3 concentrations than men with MS (79.1 ±45.4 versus 50.2±15.3 nmol/L, P=0.019 and 103.8± 36.8 versus 70.4±28.7 pmol/L, P=0.019, respectively). There was a significant positive correlation between 25(OH)D and 1,25(OH)2D 3 concentrations in all subjects (r=0.564, P=0.000), but secondary analysis revealed that the correlation was driven by women with MS (r=0.677, P= 0.001). Significant sex differences in vitamin D metabolism were observed and were most marked in individuals with MS, suggesting that vitamin D requirements may differ between the sexes, as well as by underlying disease state. Multiple Sclerosis 2007; 13: 670-672. http://msj.sagepub.com

scholarly journals HERV-K18 Env Expression and the Potential Association With TGF-β and Epstein–Barr Virus Infection in the Presence and the Absence of Vitamin D in Multiple Sclerosis Patients

2021 ◽  
Author(s):  
Tayebeh Latifi ◽  
Majid Teymoori-Rad ◽  
Ahmad Nejati ◽  
Shohreh Shahmahmoodi ◽  
Farhad Rezaei ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Real Time ◽  
Real Time Pcr ◽  
Epstein Barr Virus Infection ◽  
Healthy Controls ◽  
Increased Risk ◽  
Multiple Sclerosis Patients ◽  
Vitro Effect

Abstract Previous studies have reported that Human endogenous retroviruses (HERVs) such as HERV-K18 is associated with an increased risk of multiple sclerosis (MS). The present study aimed to evaluate the association between the expression of HERV-K18 env, TGF-β, and in vitro effect of EBV infection on the expression level of HERV-K18 env in PBMC of MS patients in both presence and absence of vitamin D (1,25-OHD). The levels of HERV-K18 env was measured in peripheral blood mononuclear cells (PBMCs) from 20 MS patients and 20 healthy controls by quantitative real-time PCR. PBMCs were further treated with EBV in the presence or the absence of vitamin D. After 72 hours, cells were collected for measurement of HERV-K18 env expression using Real-time PCR. While the expression of HERV-K18 env was significantly higher in MS patients than healthy controls, the expression of TGF–β was found to be significantly lower in MS patients compare to healthy controls. Interestingly, an inverse correlation was found between HERV-K18 env expression and TGF-β expression in MS patients but not for healthy controls. Although in vitro stimulated PBMCs with EBV showed no significant differences in terms of HERV-K18 expression, EBV infected cells revealed different patterns in the presence and the absence of vitamin D treatment. These findings not only support the important role of HERV-K18 env expression but also highlight the plausible interactions with different risk factors in MS.

scholarly journals Activity of Antimicrobial Peptide; Cathelicidin, on Bacterial Infection

2019 ◽  
Vol 13 (1) ◽  
pp. 45-53
Author(s):  
Ami Febriza ◽  
Mochammad Hatta ◽  
Rosdiana Natzir ◽  
Vivien N.A. Kasim ◽  
Hasta H. Idrus
Keyword(s):  
Vitamin D ◽  
Bacterial Infection ◽  
Antimicrobial Peptide ◽  
Active Form ◽  
Macrophage Cell ◽  
Detailed Mechanism ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Bacterial Cell Membrane ◽  
Peptide Gene

Antimicrobial peptide is an effector molecule from the natural immune system which plays a central role in defense as an antimicrobial. Cathelicidin is one of the antimicrobial peptides. Human only has one cathelicidin antimicrobial peptide called LL-37 or hCAP18. The detailed mechanism on CAMP (Cathelicidin Antimicrobial Peptide) gene regulation is still unknown, however, cathelicidin is found to have upregulation when there is bacterial infection. The most effective expression inducer of CAMP gene is 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3), which is the active form of vitamin D. Vitamin D mediates cathelicidin synthesis through the expression of Vitamin D Receptor (VDR), then the interaction activates CAMP gene to express cathelicidin. The work mechanisms of cathelicidin against bacterial infection include damaging the bacterial cell membrane, inducing autophagy process of macrophage cell, neutralizing LPS produced by bacteria, and chemotactic activities of PMNs, monocytes and lymphocytes.

scholarly journals Deficient Mineralization of Intramembranous Bone in Vitamin D-24-Hydroxylase-Ablated Mice Is Due to Elevated 1,25-Dihydroxyvitamin D and Not to the Absence of 24,25-Dihydroxyvitamin D*

Endocrinology ◽  
2000 ◽  
Vol 141 (7) ◽  
pp. 2658-2666 ◽  
Author(s):  
René St-Arnaud ◽  
Alice Arabian ◽  
Rose Travers ◽  
Frank Barletta ◽  
Mihali Raval-Pandya ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Gene ◽  
Active Form ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Physiological Importance ◽  
1,25 Dihydroxyvitamin D ◽  
Intramembranous Bone ◽  
25 Hydroxyvitamin D

The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D[ 1,25(OH)2D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a targeted inactivating mutation of the 24-OHase gene had impaired 1,25(OH)2D catabolism. Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)2D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development.

scholarly journals Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells

2013 ◽  
Vol 217 (1) ◽  
pp. 45-58 ◽  
Author(s):  
Kevin J P Ryan ◽  
Zoe C T R Daniel ◽  
Lucinda J L Craggs ◽  
Tim Parr ◽  
John M Brameld
Keyword(s):  
Vitamin D ◽  
Adipogenic Differentiation ◽  
Active Form ◽  
Muscle Cells ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Dose Dependent ◽  
Adipose Cells ◽  
Myogenic Precursor ◽  
Muscle Cell Line

Fat infiltration within muscle is one of a number of features of vitamin D deficiency, which leads to a decline in muscle functionality. The origin of this fat is unclear, but one possibility is that it forms from myogenic precursor cells present in the muscle, which transdifferentiate into mature adipocytes. The current study examined the effect of the active form of vitamin D3, 1,25-dihydroxyvitamin D3(1,25(OH)2D3), on the capacity of the C2C12 muscle cell line to differentiate towards the myogenic and adipogenic lineages. Cells were cultured in myogenic or adipogenic differentiation media containing increasing concentrations (0, 10−13, 10−11, 10−9, 10−7or 10−5 M) of 1,25(OH)2D3for up to 6 days and markers of muscle and fat development measured. Mature myofibres were formed in both adipogenic and myogenic media, but fat droplets were only observed in adipogenic media. Relative to controls, low physiological concentrations (10−13and 10−11 M) of 1,25(OH)2D3increased fat droplet accumulation, whereas high physiological (10−9 M) and supraphysiological concentrations (≥10−7 M) inhibited fat accumulation. This increased accumulation of fat with low physiological concentrations (10−13and 10−11 M) was associated with a sequential up-regulation ofPPARγ2(PPARG) andFABP4mRNA, indicating formation of adipocytes, whereas higher concentrations (≥10−9 M) reduced all these effects, and the highest concentration (10−5 M) appeared to have toxic effects. This is the first study to demonstrate dose-dependent effects of 1,25(OH)2D3on the transdifferentiation of muscle cells into adipose cells. Low physiological concentrations (possibly mimicking a deficient state) induced adipogenesis, whereas higher (physiological and supraphysiological) concentrations attenuated this effect.

scholarly journals Characteristics of Serum Ratios of 1,25-Dihydroxyvitamin D to 25-Hydroxyvitamin D for Assessment of Bone Metabolism

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A272-A273
Author(s):  
Koichiro Yamamoto ◽  
Manami Fujita ◽  
Hiroyuki Honda ◽  
Yoshihisa Hanayama ◽  
Kazuki Tokumasu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Metabolism ◽  
Active Form ◽  
The Body ◽  
Ultraviolet B ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Gender Specific

Abstract Vitamin D is obtained in the body by food intake or by production from 7-dehydrocholesterol by exposure of the skin to ultraviolet B radiation. It is first metabolized in the liver to 25-hydroxyvitamin D (25D), which is a major circulating metabolite. In the kidney, 25D is subsequently metabolized to the hormonally active form, 1,25-dihydroxyvitamin D (1,25D), via 1α-hydroxylase encoded by the CYP27B1 gene. 1,25D has a cellular effect through the vitamin D receptor, which leads to calcium absorption in the gut, bone metabolism, and parathyroid function. A recent study showed that a low vitamin D status is common worldwide and is associated with various diseases including kidney, heart, and liver failure, secondary hyperparathyroidism, osteomalacia, inflammatory bowel disease, granuloma-forming disorders (sarcoidosis and tuberculosis), and cancer. Vitamin D deficiency also increases the risks of falls, fractures, bone loss, sarcopenia, leading to worse outcomes of illness severity, morbidity, and mortality. The 1,25D/25D ratio is considered to be a useful tool for diagnosis of ocular sarcoidosis; however, its clinical utility and relevance to pathophysiology of evaluation of the ratio 1,25D/25D which indicates vitamin D activation have remained unknown. To clarify the clinical usefulness of markers for vitamin D activation, 87 patients in whom serum 25D and 1,25D level was measured were retrospectively reviewed in the present study. Data for 79 patients (33 males and 46 females) were analyzed after exclusion of 8 patients taking vitamin D. The median serum 1,25D/25D ratio was significantly lower in males than in females: 4.1 (IQR: 2.3–5.8) x 10−3 versus 6.8 (3.0–9.8) x 10−3. However, individual levels of 25D and 1,25D were not different in males and females. The major categories of main disorders were endocrine (30.6 %), inflammatory (18.5 %), and bone-related (16.7 %) disorders. The ratios of serum 1,25D/25D had significant negative correlations with femoral dual energy X-ray absorptiometry % young adult mean (DEXA %YAM) (R=-0.35) and lumbar DEXA %YAM (R=-0.32). Significant correlations were found between 1,25D/25D ratio and serum levels of inorganic phosphate (R=-0.34), intact parathyroid hormone (R=0.64) and alkaline phosphatase (R=0.46) in all patients. Of interest, the 1,25D/25D ratio had gender-specific characteristics: the ratio had a significant correlation with age in males (R=0.49), while it had a significant correlation with body mass index (BMI) in females (R=0.34). Collectively, the results revealed that the ratio of serum 1,25D/25D as a marker for activation of vitamin D had relevance to clinical parameters, especially bone turnover, with gender-specific features. It is suggested that the existence of a gender-specific difference of aging males and obese females regarding the activation of vitamin D that is functionally linked to bone metabolism.

scholarly journals MON-388 Total and Free 1,25dihydroxyvitamin D Levels in Postmenopausal Patients with Primary Hyperparathyroidism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lingqiong Meng ◽  
Sue A Shapses ◽  
Xiangbing Wang
Keyword(s):  
Vitamin D ◽  
Primary Hyperparathyroidism ◽  
Active Form ◽  
Serum Levels ◽  
Accurate Estimate ◽  
Biologically Active ◽  
Free Form ◽  
Vitamin D Metabolites ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

Abstract Background: Vitamin D3 is metabolized to 25-hydroxyvitamin D [25(OH)D] in liver, and only after it goes to kidney is it converted to its biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Also, the majority of both total 25(OH)D and 1,25(OH)2D are tightly bound to vitamin D bind protein (DBP) and only a small portion remains in free form. In certain patient populations, like primary hyperparathyroidism (PHPT), concentrations of free vitamin D metabolites may be affected by altered levels of binding protein. Objective: To evaluate total and free 1,25(OH)2D levels in PHPT patients and healthy controls. Methods: Thirty female patients with PHPT and 30 healthy age and body mass index (BMI) matched controls were enrolled (57.1 ± 9.8 years and BMI of 32.2 ± 7.2 kg/m2). Serum levels of calcium, intact parathyroid hormone (iPTH), DBP, total 25(OH)D and 1,25(OH)2D levels were examined. Serum free 25(OH)D and 1,25(OH)2D levels were calculated using equations adapted from Bikle et al. Results: There were no significant differences in age and BMI between groups. Compared to controls, patients with PHPT had lower total 25(OH)D (25.2 ± 7.5 vs. 19.3 ± 6.4 ng/mL; p <0.001) and DBP levels (40.7± 3.1 vs. 36.5 ± 5.7 mg/dL; p <0.001). There were no significant differences in total 1,25(OH)2D levels or calculated free 25(OH)D levels between PHPT patients and controls; but the calculated free 1,25(OH)2D levels were 27% higher in the PHPT patients compared to controls (p<0.001). The calculated free (but not total) 1,25(OH)2D level was inversely correlated with DBP (r=-0.35, p<0.01) and positively correlated with iPTH levels (r=0.33, p<0.01). Conclusion: Postmenopausal patients with PHPT had lower serum total 25(OH)D, but similar free 25(OH)D levels. In contrast, total 1,25(OH)2D levels did not differ between patients and controls; however, patients had higher free 1,25(OH)2D. Because total 25(OH)D and 1,25(OH)2D levels do not reflect free levels, standard clinical measures of circulating vitamin D may not be an accurate estimate of true vitamin D status in patients with PHPT. References: Bikle et al. Serum Protein Binding of 1,25-Dihydroxyvitamin D: A Reevaluation by Direct Measurement of Free Metabolite Levels. JCEM 1985;61:969-75.

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR): clinical heterogeneity and long-term efficacious management of eight patients from four unrelated Arab families with a loss of function VDR mutation

2018 ◽  
Vol 31 (8) ◽  
pp. 861-868 ◽  
Author(s):  
Muhammad Faiyaz-Ul-Haque ◽  
Waheeb AlDhalaan ◽  
Abdullah AlAshwal ◽  
Bassam S. Bin-Abbas ◽  
Afaf AlSagheir ◽  
...  
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Clinical Symptoms ◽  
Active Form ◽  
Loss Of Function ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Vitamin D Resistant Rickets ◽  
Resistant Rickets

Abstract Background: Vitamin D regulates the concentrations of calcium and phosphate in blood and promotes the growth and remodeling of bones. The circulating active form of vitamin D, 1,25-dihydroxyvitamin D, binds to the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor to regulate the expression of target genes. Inactivating mutations in the VDR gene cause hereditary vitamin D-resistant rickets (HVDRR), a rare disorder characterized by an early onset of rickets, growth retardation, skeletal deformities, hypocalcemia, hypophosphatemia and secondary hyperparathyroidism, and in some cases alopecia. Methods: We describe eight new HVDRR patients from four unrelated consanguineous families. The VDR gene was sequenced to identify mutations. The management of patients over a period of up to 11 years following the initial diagnosis is assessed. Results: Although all patients exhibit main features of HVDRR and carry the same c.885C>A (p.Y295*) loss of function mutation in the VDR gene, there was heterogeneity of the manifestations of HVDRR-associated phenotypes and developmental milestones. These eight patients were successfully treated over a period of 11 years. All clinical symptoms were improved except alopecia. Conclusions: The study concludes that VDR sequencing and laboratory tests are essential to confirm HVDRR and to assess the effectiveness of the treatment.

Clinical and Serological Biomarkers of Treatment’s Response in Multiple Sclerosis Patients Treated Continuously with Interferonβ-1b for More than a Decade

2018 ◽  
Vol 17 (10) ◽  
pp. 780-792 ◽  
Author(s):  
Laura Iulia Bărcuţean ◽  
Andreea Romaniuc ◽  
Smaranda Maier ◽  
Zoltan Bajko ◽  
Anca Moţăţăianu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demographic Data ◽  
Active Form ◽  
Positive Influence ◽  
Serum Samples ◽  
Disability Score ◽  
Positive Correlations ◽  
Multiple Sclerosis Patients ◽  
Factor Α ◽  
Serological Biomarkers

Introduction: We evaluated the peripheral immune panel of Multiple Sclerosis (MS) patients treated for more than 10 years with interferon-beta1b (IFNβ-1b) and aimed to identify possible biomarkers of treatment response. Material and Methods: Serum samples from 70 MS patients treated with IFNβ-1b more than a decade were analysed for 15 cytokines, that were correlated with the disability score, annual relapse ratio (ARR): the total number of relapses-ARR_0, relapse on treatment-ARR_1 and demographic data. Two groups were defined based on the levels of disability, calculated using the Expanded Disability Status Scale (EDSS): G1 – recurrent-remissive and G2 – secondary-progressive. Furthermore, we split the patients based on gender (G1_f, G1_m, G2_f, G2_m). Results: The ARR was reduced after treatment was instituted. We found positive correlations between IL_25 and EDSS in G1_f and G2_f, tumor necrosis factor α (TNFα) and ARR_1 and ARR_0 in G1, and IL_17F with ARR_1. Negative correlations were for IL_25 and ARR_0 and ARR_1. SCD40L intensely positively correlated with IL_31 in G1 and G2. Conclusion: After more than a decade of treatment, IFNβ-1b offers good results by reducing relapses and slowing disability progression. Several biomarkers can be used to assess the patient’s response. High levels of IL_17 and TNFα will indicate a more active form of the disease. IL-25 may exert a positive influence in male MS patients and should be considered for future studies, together with the co-modulation between sCD40L and IL_31. Our method allowed us to screen the peripheral immune panel and can be used for assessing the peripheral levels of the above-mentioned cytokines.

scholarly journals Two Vitamin D Response Elements Function in the Rat 1,25-Dihydroxyvitamin D 24-Hydroxylase Promoter

1995 ◽  
Vol 270 (4) ◽  
pp. 1675-1678 ◽  
Author(s):  
Claudia Zierold ◽  
Hisham M. Darwish ◽  
Hector F. DeLuca
Keyword(s):  
Vitamin D ◽  
Response Elements ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D
Sign in / Sign up

Export Citation Format

Share Document