Vitamin D Binding Protein Research Articles

Calcitriol Concentration in the Early Phase of Myocardial Infarction and Its Relation to Left Ventricular Ejection Fraction

Vitamin D deficiency is one of the most common metabolic disorders in the European population. A low level of 25-OH vitamin D3 is related to an elevated risk of myocardial infarction (MI). The aim of our study was to examine the relationship between calcidiol and calcitriol serum concentration and left ventricular ejection fraction early after interventional treatment for acute coronary syndrome. A total of 80 patients diagnosed with MI, who underwent primary percutaneous coronary intervention, were included in the study. Blood samples for calcidiol, calcitriol, and vitamin D-binding protein were obtained 24 h after primary PCI and were measured using an enzyme-linked immunosorbent assay. Only 9% of patients had a proper level of 25-OHD3 in the serum (30–80 ng/mL). A total of 16% of patients revealed a suboptimal concentration of 25-OHD3 (20–30 ng/mL), and in 75% of patients, the concentration of 25-OHD3 was lower than 20 ng/mL. Moreover, patients with left ventricle ejection fraction of < 40% had significantly lower concentrations of calcidiol and calcitriol. A low calcitriol serum concentration affects post-MI left ventricle ejection fraction early after myocardial infarction onset. It seems that 1.25(OH)D3 may contribute to acute myocardial infarction; however, there are insufficient clinical trials related to this topic, and the available evidence is mainly from in vitro studies. We hope these preliminary reports will provide a better understanding of post-MI.

Polymorphisms rs7041 (c.1296T>G) and rs4588 (c.1307C>A) and Distribution of Gc Variants in a Population of Hemodialysis Patients in Abidjan

Background: Vitamin D deficiency is associated with chronic kidney disease (CKD). Renal failure patients are routinely supplemented with vitamin D to compensate for this deficiency. The response to vitamin D supplementation can vary according to variants in the Gc (Vitamin D-binding protein) gene. The combination of two single-nucleotide polymorphisms (SNPs), rs7041 (c.1296T>G) and rs4588 (c.1307C>A), in the Gc gene forms three variants, namely Gc1f (c.1296 T, c.1307C), Gc1s (c.1296G, c.1307C), Gc2 (c.1296T, c.1307A), which result in six vitamin D-binding protein (DBP) phenotypes. Significant variations in variant frequency are reported in different populations. Objectif: The aim of our study was to determine the distribution of Gc genotypes and variants in a population of haemodialysis patients. Methods and Results: Genomic DNA from forty-eight blacks Africans adults with CKD were extracted from whole blood samples. The DNA region spanning the two SNPs of interest was amplified by PCR. The amplified DNA was subjected to the action of restriction enzymes, StyI and HaeIII in two different reactions. Genotyping was performed by analysis of the length of restriction fragments by 2.5% agarose gel electrophoresis. The mean age of the study population was 42±12 years, with a sex ratio of 1.6. The C/C genotype of rs4588 (c.1307C>A) was the most frequent, followed by the T/T genotype (90.6%) of rs7041 (c.1296T>G). Three DBP phenotypes, Gc1f-1f (c.1296T, c.1307C/p.432Asp, p.436Thr): 89.6 %, Gc1s-1s (c.1296 G, c.1307C/p.432Glu, p.436Thr): 8.3 %, and Gc1f/Gc1s: 2,1% were identified. Conclusion: Finally, the Gc1f variant was the most frequent. Our results suggest the need for vitamin D testing to establish the correlation between the observed Gc genotypes/variants and vitamin D status in the study population.

Free 25(OH)D3 levels in follicular ovarian fluid top-quality embryos are higher than non-top-quality embryos in the normoresponders group

Vitamin D and calcium in follicular fluid play an important role in modulating steroidogenesis, folliculogenesis, and oocyte quality determination. Both collaborate to produce top-quality embryos (TQE) during in vitro fertilization (IVF). In this study, we compared free 25(OH)D3 and calcium levels in follicular fluid between TQE and non-TQE groups. This cross-sectional study included women who underwent IVF procedures at tertiary hospitals in Bandung, Indonesia. Ovarian follicular fluid was collected during the ovum pick-up procedure. The examination of 25(OH)D3 levels, vitamin d-binding protein, and calcium in the follicles was done using an enzyme-linked immunosorbent assay (ELISA). Free 25(OH)D3 levels were calculated using the Vermeulen formula. A total of 173 samples met the study criteria, including 86 subjects in the TQE group and 87 subjects in the non-TQE group. There was a significant difference in free 25(OH)D3 follicular fluid levels between the TQE and non-TQE groups (p = 0.017); however, there was no significant difference in calcium levels between the two groups (p = 0.805). We also found that there was a significant association between free 25(OH)D3 follicular fluid levels and embryo quality (OR 3.05, 95% CI 1.46–6.38; p-value = 0.002); however, there was no significant association between follicular fluid calcium and embryo quality [p = 0.144 and OR, 1.74 (95% CI 0.82–3.68)]. The results suggest that free 25(OH)D3 and calcium in the follicular fluid act independently during steroidogenesis, folliculogenesis, and fertilization.

The association of the rs4588 and rs7041 polymorphisms of the VDBP gene and vitamin D status in obese individuals

BACKGROUND: Vitamin D (VD) plays an important role in bone metabolism, regulating phosphorus and calcium in the body. The VD binding protein (VDBP) binds to VD metabolites and transports them to the target tissues; it is assumed that polymorphisms of this gene influence the absorption of VD in the body. However, the relationship between polymorphisms of the VDBP gene and blood VD levels in obesity has not yet been sufficiently investigated. AIM: To identify the relationship of blood VD content (form 25(OH)D3) of obese and non-obese persons and the VDBP gene polymorphisms rs4588 and rs7041. METHODS: 80 residents of the Kaliningrad region participated in the study. The participants were divided according to VD status (norm, insuffient, deficiency and severe deficiency) and body mass index (BMI). Blood VD levels were determined using an ELISA. Genomic DNA was isolated from whole blood. Restriction analysis was performed with the endonucleases HaeIII and ErhI to determine the VDBP gene polymorphisms. RESULTS: There were no significant differences in blood VD levels of obese and non-obese individuals. Within the genotypes of the rs4588 polymorphism (CA), VD levels did not differ in individuals with different BMI (CС p=0.186; CA p=0.350, AA data is insufficient). However, when analyzing the allele frequencies in groups with different VD status, a significant difference was found in all groups compared to the control (insufficient p=0.009; deficiency p=0.010; severe deficiency p0.001). When analyzing the rs7041 polymorphism of the VDBP gene (TG), splitting groups by BMI within specific genotypes did not reveal differences in VD levels (TG p=0.150; GG p=0.087; TT data is insufficient), but we found a significant difference between control and severe deficiency (p0.001) based on allele frequencies of the rs7041 polymorphism. CONCLUSION: The VD content in blood of the obese individuals was comparable to that of the control group. The presence of the VDBP gene rs7041 and rs4588 polymorphisms has no influence on blood VD level, regardless of BMI. However, allele A of the rs4588 polymorphism is associated with an unfavorable VD status, while allele G of the rs7041 polymorphism is associated with normal blood VD levels.

Genetic variations in Vitamin D Binding Protein (VDBP) impact vitamin D level and asthma susceptibility across the four ethnic populations.

Asthma are associated with the vitamin D axis. Genetic variations of VDBP, notably rs7041 and rs4588, influence circulating vitamin D levels. However, data on their link to asthma are inconsistent, and ethnic differences remain unclear. We explored how genetic variations in VDBP affect vitamin D levels and susceptibility to asthma across diverse ethnic populations. In our cross-ethnic study, we analyzed vitamin D levels and VDBP polymorphisms (rs7041 and rs4588) in Taiwanese, Mongolian, Lithuanian, and Latvian populations. Our study included 363 asthmatic subjects and 481 non-asthma controls. We performed genotyping for rs7041 and rs4588 and assessed serum concentrations of 25-hydroxyvitamin D [25(OH)D], examining the associations between VDBP polymorphisms, vitamin D levels, and asthma. The study found significant differences in vitamin D levels among ethnic groups. Non-asthmatic individuals from Taiwan had higher concentrations, while asthma subjects in both Taiwanese and Lithuanian populations showed lower levels compared to their non-asthma counterparts (both p-value < 0.001). VDBP polymorphisms were associated with asthma in the Latvian population, with the rs7041 GG vs. GT+TT showing an odds ratio (OR) of 1.72 (95% confidence interval (CI): 1.10-2.69, p = 0.016) and the rs4588 CC vs. CA+AA showing an OR of 1.88 (95%CI: 1.24-2.84, p = 0.003). However, this association was not observed in other populations. Our cross-ethnic study underscores the intricate relationship between VDBP genetic variations, vitamin D levels, and asthma vulnerability. The association of VDBP polymorphisms with asthma seems to differ among populations, emphasizing the importance of a nuanced comprehension of these connections.

Polymorphisms of the Vitamin D Binding Protein (VDBP) and Free Vitamin D in Patients with Cystic Fibrosis.

Vitamin D-binding protein (VDBP) and free vitamin D are new markers that are being studied as a possible markers of vitamin D status. The main aim of our study was to analyze the VDBP genotype and quantify the levels of free vitamin D in a sample of cystic fibrosis (CF) patients. We conducted a multicenter, cross-sectional, and prospective study including patients with CF and exocrine pancreatic insufficiency who were clinically stable. We investigated vitamin D levels (total and free) and the different VDBP haplotypes. Free vitamin D levels were measured using an electro-chemiluminescence assay. A sample of 48 patients was obtained (52% male; median age 13.8 years). The most common allele of VDBP was Gc1s (72%) > Gc2 (52%) > Gc1f (27%). The median calcidiol was 21.2 ng/mL (IR 15.3-26.9), and 81% had levels in the insufficiency range: 23 patients (48%) below 20 ng/mL, and 16 (33%) between 20 and 30 ng/mL. The median free vitamin D level was 4.2 pg/mL (IR 3.9-5.6). A positive correlation was observed between calcidiol and free vitamin D levels (r = 0.871; p < 0.0001). After adjustment for season, vitamin D supplementation, sex, and CF-related diabetes, patients with Gc1f polymorphism had a lower risk of vitamin D deficiency, OR 0.22 (95% CI 0.05-0.99), and p = 0.027. A negative linear trend was observed between the polymorphisms grouped into three categories (Gc1/Gc1, Gc1/Gc2, and Gc2/Gc2, in that order) and vitamin D and free vitamin D levels (p = 0.025 and p = 0.033, respectively). In CF, as in the general population, the most common VDBP haplotype in the Caucasian race is Gc1s. VDBP polymorphisms influence serum vitamin D and free vitamin D levels in CF patients. There is a good correlation between free vitamin D and calcidiol levels, suggesting that measuring the latter in CF does not seem to provide any additional benefit.

8381 The Pro-atrophic Effect of Vitamin D Binding Protein in Skeletal Muscle and Its Involvement in Cancer-Induced Muscle Wasting

Abstract Disclosure: N. Filigheddu: None. T. Raiteri: None. S. Reano: None. A. Scircoli: None. A. Antonioli: None. F. Prodam: None. Vitamin D binding protein (VDBP), encoded by the Gc gene, is a multifunctional serum glycoprotein synthesized by hepatocytes, whose primary function is the transport of vitamin D metabolites in the bloodstream. In addition, VDBP enhances the chemotactic activity of neutrophil chemoattractants and takes part in the actin-scavenger system by acting as a monomeric G-actin-binding protein. Several studies have reported a correlation between increased levels of VDBP and various pathologies often associated with muscle wasting, including different types of tumors. Given these findings, we hypothesized that VDBP may play a role in skeletal muscle homeostasis.In vitro, treatment of C2C12 myotubes with 100 mM VDBP for 24 h induced the perturbation of intracellular actin dynamics due to VDBP's ability to bind G-actin that, in turn, led to mitochondrial dysfunction (i.e., mitochondrial membrane potential dissipation, respiratory impairment, increased ROS production, induction of the fission machinery), exacerbation of autophagy, and, eventually, atrophy, seen as the reduction of myotube diameter. Remarkably, pharmacological intervention on myotubes with jasplakinolide (250 mM, 30 min pre-treatment) to counteract VDBP effects on intracellular actin dynamics was sufficient to prevent VDBP-induced atrophy. To assess if VDBP had a causative role in muscle atrophy in vivo, we injected VDBP (1.5 mg/Kg) every 48 h for one week in the tibialis anterior muscles of Gc knock-out mice (VDBP KO). At the end of the experimental period, we observed the induction of the mitophagic gene Bnip3, impairment of muscle performances (26% reduction of grip strength at the endpoint), and a 16% reduction of muscle mass compared to the saline-injected contralateral muscles, confirming the atrophic effect of VDBP in vivo.Coherently with the upregulation of VDBP observed in cancer patients, VDBP levels also increase in murine models of cancer cachexia. To test the hypothesis that VDBP could play a role in cancer-associated muscle wasting, we induced cancer cachexia in VDBP KO mice by inoculating 106 Lewis Lung Carcinoma (LLC) cells resuspended in 100 μl of saline on the back of mice. Tumor-bearing VDBP KO mice preserved their body weight and performances, and the muscle loss was lessened by more than 50% compared to cachectic WT mice. Notably, between the two groups, there were no differences in tumor growth or food intake, ruling out the possibility that the reduction in muscle wasting could depend on smaller tumors or differential development of anorexia in the two genotypes. In conclusion, we demonstrated that VDBP acts as a hormone per se, having a direct pro-atrophic activity on skeletal muscle. Our data suggest that VDBP could represent a potential therapeutic target to treat cancer cachexia and other pathologies in which the rise of VDBP could impinge muscle mass and functionality. Presentation: 6/1/2024

9268 The Pro-atrophic Effect of Vitamin D Binding Protein in Skeletal Muscle and Its Involvement in Cancer-Induced Muscle Wasting

Abstract Disclosure: N. Filigheddu: None. T. Raiteri: None. S. Reano: None. A. Scircoli: None. A. Antonioli: None. F. Prodam: None. Vitamin D binding protein (VDBP), encoded by the Gc gene, is a multifunctional serum glycoprotein synthesized by hepatocytes, whose primary function is the transport of vitamin D metabolites in the bloodstream. In addition, VDBP enhances the chemotactic activity of neutrophil chemoattractants and takes part in the actin-scavenger system by acting as a monomeric G-actin-binding protein. Several studies have reported a correlation between increased levels of VDBP and various pathologies often associated with muscle wasting, including different types of tumors. Given these findings, we hypothesized that VDBP may play a role in skeletal muscle homeostasis.In vitro, treatment of C2C12 myotubes with 100 mM VDBP for 24 h induced the perturbation of intracellular actin dynamics due to VDBP's ability to bind G-actin that, in turn, led to mitochondrial dysfunction (i.e., mitochondrial membrane potential dissipation, respiratory impairment, increased ROS production, induction of the fission machinery), exacerbation of autophagy, and, eventually, atrophy, seen as the reduction of myotube diameter. Remarkably, pharmacological intervention on myotubes with jasplakinolide (250 mM, 30 min pre-treatment) to counteract VDBP effects on intracellular actin dynamics was sufficient to prevent VDBP-induced atrophy. To assess if VDBP had a causative role in muscle atrophy in vivo, we injected VDBP (1.5 mg/Kg) every 48 h for one week in the tibialis anterior muscles of Gc knock-out mice (VDBP KO). At the end of the experimental period, we observed the induction of the mitophagic gene Bnip3, impairment of muscle performances (26% reduction of grip strength at the endpoint), and a 16% reduction of muscle mass compared to the saline-injected contralateral muscles, confirming the atrophic effect of VDBP in vivo.Coherently with the upregulation of VDBP observed in cancer patients, VDBP levels also increase in murine models of cancer cachexia. To test the hypothesis that VDBP could play a role in cancer-associated muscle wasting, we induced cancer cachexia in VDBP KO mice by inoculating 106 Lewis Lung Carcinoma (LLC) cells resuspended in 100 μl of saline on the back of mice. Tumor-bearing VDBP KO mice preserved their body weight and performances, and the muscle loss was lessened by more than 50% compared to cachectic WT mice. Notably, between the two groups, there were no differences in tumor growth or food intake, ruling out the possibility that the reduction in muscle wasting could depend on smaller tumors or differential development of anorexia in the two genotypes. In conclusion, we demonstrated that VDBP acts as a hormone per se, having a direct pro-atrophic activity on skeletal muscle. Our data suggest that VDBP could represent a potential therapeutic target to treat cancer cachexia and other pathologies in which the rise of VDBP could impinge muscle mass and functionality. Presentation: 6/1/2024

Serum 25-hydroxyvitamin D, genetic susceptibility and abdominal aortic aneurysm risk.

The association of serum 25-hydroxyvitamin D [25(OH)D] and genetic polymorphisms of the vitamin D receptor (VDR), and the vitamin D binding protein (VDBP) with incident abdominal aortic aneurysm (AAA) remains uncertain. To investigate whether serum 25(OH)D, genetic polymorphisms of VDR and VDBP, genetic susceptibility to AAA, and the interactions among these factors influence the risk of incident AAA. Retrospective cohort study. UK Biobank. 447,529 participants without a diagnosis of prevalent aortic aneurysm or aortic dissection at baseline. Serum 25(OH)D concentration. Incident AAA. During a median follow-up of 12.5 years, 2,042 participants developed incident AAA. A significant inverse association between serum 25(OH)D and incident AAA was observed (per SD increment, HR, 0.92; 95%CI, 0.88-0.96), which was particularly pronounced in older individuals and those without diabetes (both P for interaction <0.05). Compared to participants with serum 25(OH)D ≥ 50 nmol/L, those with serum 25(OH)D between 25 and <50 nmol/L and <25 nmol/L exhibited a significant higher risk of incident AAA. In the 371,621 participants with genetics assessment, individuals carrying AA alleles of ApaI SNP had a significant increased risk of incident AAA compared to those carrying CC alleles (HR, 1.16; 95%CI, 1.02-1.32). The inverse association between serum 25(OH)D and incident AAA was stronger in individuals with intermediate or high genetic risk for AAA (P for interaction = 0.048). There was a significant inverse association between serum 25(OH)D and AAA incidence, particularly among individuals with higher genetic risk for AAA, older age, and without diabetics.

Urinary Complement C3 and Vitamin D-Binding Protein Predict Adverse Outcomes in Patients with Acute Kidney Injury after Cardiac Surgery

Introduction: Acute kidney injury (AKI) is associated with adverse outcomes, including death and dialysis. The goal of this study was to identify prognostic biomarkers of AKI that could be used across multiple phenotypes of AKI and across different species. Methods: Liquid chromatography/tandem mass spectrometry analysis of urine samples from three species (human, rat, and mouse) and four etiologies of AKI identified five potential biomarkers, of which two were validated, complement C3 and vitamin D-binding protein, in a cohort of 157 patients that developed AKI following cardiothoracic surgery. We studied the relationship between the biomarker’s concentration in the urine and the development of a composite primary endpoint (stage 3 AKI within 10 days or death within 30 days). Results: Of the 153 patients who developed AKI following cardiovascular surgery, 17 met the combined primary outcome. The median concentration of urine complement C3 adjusted to urine creatinine had the best predictive value and was significantly higher in the primary outcome group than in the controls. Similarly, the median concentration of vitamin D-binding protein was higher in the primary outcome group. Conclusions: The studies provide proof in principle that cross-species discovery analyses could be a valuable tool for identifying novel prognostic biomarkers in AKI. Urine complement C3 and vitamin D-binding protein could be promising early predictors of adverse outcomes in patients who develop AKI after cardiac surgery.

Investigation of the Relationship between Vitamin D Deficiency and Vitamin D-Binding Protein Polymorphisms in Severe COVID-19 Patients.

This study explores the association of vitamin D-binding protein (VDBP) gene polymorphisms, vitamin D levels, and the severity of COVID-19, including the need for intensive care unit (ICU) hospitalization. We analyzed a cohort of 56 consecutive age- and gender-matched adult COVID-19-positive patients and categorized them into three groups: outpatients with mild illness, inpatients with moderate disease, and ICU patients. We measured levels of free, total, and bioavailable 25-hydroxyvitamin D [25(OH)D], VDBP, and albumin. VDBP polymorphisms rs5488 and rs7041 were identified using real-time PCR. A significant proportion of ICU patients were vitamin D-deficient (56.25%) compared to outpatients (10%) and inpatients (5%) (p = 0.0003). ICU patients also had notably lower levels of VDBP (median: 222 mg/L) and total 25(OH)D (median: 18.8 ng/mL). Most patients carried heterozygous rs7041 (60.7%) and wild-type rs4588 (58.9%) genotypes. The distribution of rs7041 SNP varied significantly among groups (p = 0.0301), while rs4588 SNP distribution did not (p = 0.424). Heterozygous rs4588 patients had significantly lower VDBP levels (p = 0.029) and reduced bioavailable 25(OH)D compared to those with wild-type rs4588 (p = 0.020). Our findings indicate that VDBP gene polymorphisms, particularly rs7041 and rs4588, are associated with vitamin D status and the severity of COVID-19. The lower VDBP levels and bioavailable vitamin D in ICU patients suggest that these genetic variants may influence disease severity and hospitalization needs. These results highlight the potential role of VDBP polymorphisms in COVID-19 severity, suggesting that genetic screening could be valuable in assessing the risk of severe outcomes and guiding personalized treatment strategies.

P.327: Urinary vitamin D binding protein (VDBP) as a biomarker in systemic lupus erythematosus patients with lupus nephritis and its relation to renal activity.

P.327: Urinary vitamin D binding protein (VDBP) as a biomarker in systemic lupus erythematosus patients with lupus nephritis and its relation to renal activity.

Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

Relation of T Cell Profile with Vitamin D Receptor and Vitamin D-Binding Protein Gene Polymorphisms in Atopy.

Atopic diseases, including atopic dermatitis (AD) and allergic asthma (AA), are characterized by complex immune responses involving various T cells subsets and their cytokine profiles. It is assumed that single nucleotide polymorphisms (SNPs) in the Vitamin D receptor (VDR) gene and the Vitamin D-binding protein (GC) gene are related to the action of Vitamin D and, consequently, play a role in regulating the immune response. However, there is not enough data to unequivocally support the hypothesis about the relationship between T cells profile and VDR or GC SNPs. Two hundred sixty-six subjects (aged > 18 years) were involved in the study: 100 patients with mild or moderate AD, 85 patients with mild or moderate AA, and 81 healthy individuals. Blood cell counts were determined by standard methods. Flow cytometric analysis was used to evaluate CD4+ T-helper (Th) cell subtypes: Th2, Th1, Th17, and T regulatory (Treg) cells in peripheral blood. Measurements of cytokines, total immunoglobulin E (IgE), and Vitamin D levels in serum were evaluated by ELISA. Significantly higher levels of Th1, Th2, and Th17 cells, along with lower levels of Tregs, were found in patients with atopic diseases compared to healthy individuals. Additionally, higher serum levels of interleukin (IL) 5, IL-17A, and transforming growth factor-β1 (TGF-β1), as well as lower levels of IL-10, were observed in patients with atopic diseases than in control. The study established associations between VDR SNPs and immune profiles: the AA genotype of rs731236 was associated with increased Th2 and Th17 cells and a higher Th1/Th2 ratio; the GG genotype of rs731236 was linked to decreased serum IL-10 and TGF-β1 levels; and the TT genotype of rs11168293 was associated with increased IL-10 levels. Additionally, the GG genotype of GC gene SNP rs4588 was associated with reduced Th2 and Th17 lymphocytes, while the TT genotype of rs4588 was linked to decreased IL-10 levels. Furthermore, the CC genotype of rs7041 was associated with higher levels of Th2, Th17, IL-10, and IL-35, as well as reduced levels of TGF-β1, while the GG genotype of rs3733359 was associated with reduced IL-10 levels. In conclusion, our study demonstrates that the Vitamin D receptor gene single nucleotide polymorphisms rs731236 and rs11168293, along with polymorphisms in the Vitamin D-binding protein gene (rs4588, rs7041, rs3733359), are significantly associated with variations in T cell profiles in atopy. These variations may play a crucial role in promoting inflammation and provide insight into the genetic factors contributing to the pathogenesis of atopy.

Proteomic Profiling of HDL in Newly Diagnosed Breast Cancer Based on Tumor Molecular Classification and Clinical Stage of Disease.

The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.

The Effect of Phototherapy on Systemic Inflammation Measured with Serum Vitamin D-Binding Protein and hsCRP in Patients with Inflammatory Skin Disease.

Vitamin D plays a role in inflammatory skin disease, but the exact mechanisms and the clinical significance remain unclear. According to the free hormone hypothesis, it is the free concentration of 25-hydroxy vitamin D (25(OH)D) that is biologically active. Vitamin D-binding protein (DBP) acts as the major transporter of vitamin D in the circulation, and DBP concentration defines the free 25(OH)D levels. DBP levels are elevated in various inflammatory conditions, including psoriasis. Narrowband-ultraviolet B (NB-UVB) is the most widely used phototherapy and is an established first-line treatment for psoriasis and atopic dermatitis (AD), often used before proceeding to systemic treatment. The aim of this study was to investigate the influence of NB-UVB phototherapy on DBP and high-sensitivity C-reactive protein (hsCRP) levels, as markers of systemic inflammation, in inflammatory skin disease. Thirty adults (psoriasis (n = 20) and AD (n = 10)) were treated with NB-UVB. Serum DBP, hsCRP, total and free 25(OH)D, and 1,25-dihydroxy vitamin D (1,25(OH)2D) were measured before and after NB-UVB. Disease severity was assessed with Psoriasis Area and Severity Index (PASI), SCORing Atopic Dermatitis (SCORAD), and Visual Analogue Scale (VAS). DBP decreased in psoriasis patients and varied with no clear trend in AD patients. HsCRP decreased in both groups, but this did not reach statistical significance. PASI, SCORAD, and VAS improved, and vitamin D levels increased after NB-UVB. Sub-analysis indicated a better response to NB-UVB for patients with vitamin D deficiency and insufficiency compared to vitamin D-sufficient patients. The decrease in DBP after NB-UVB in psoriasis patients suggests a potential systemic anti-inflammatory effect of phototherapy. Measurement of vitamin D levels may potentially serve as a tool to identify patients who would derive the greatest benefit from NB-UVB phototherapy.

25-Hydroxyvitamin D, Vitamin D Binding Protein and Gestational Diabetes Mellitus: A Two-Sample Mendelian Randomization Study.

Numerous studies have examined whether vitamin D is associated with gestational diabetes mellitus (GDM). Nevertheless, it is still challenging to determine the causality, due to a number of shortcomings in observational research and randomized controlled trials. Mendelian randomization (MR) with two samples was conducted to investigate the potential causative association between 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (VDBP) and GDM risk. Publicly accessible summary data from independent cohorts were used for two-sample MR. For 25(OH)D, we obtained data from UK Biobank, IEU and EBI, then performed a meta-analysis to enhance the statistical power (via METAL); for VDBP, data were obtained from the INTERVAL study; for GDM, data were obtained from FinnGen. The inverse variance weighted (IVW) approach was performed as the main analysis, together with several sensitivity analyses, such as MR-Egger, maximum likelihood, weighted median, and weighted mode. The IVW results revealed a weak negative causal connection between 25(OH)D and GDM risk [OR (95% CI) = 0.71 (0.50, 0.99), p = 0.046]. However, the causal association was unstable according to sensitivity analyses, and Cochran's Q test revealed significant heterogeneity. After removing BMI-related IVs, the causal association between 25(OH)D and GDM disappeared [OR (95% CI) = 0.76 (0.55, 1.06), p = 0.101]. In addition, our study found no proof to support the assumption that VDBP level was related to GDM risk causally [OR (95% CI) = 0.98 (0.93, 1.03), p = 0.408]. According to this study, a weak negative causal association between 25(OH)D and GDM risk was found, while we had little proof to support the link between VDBP and GDM. To further explore whether total or free 25(OH)D levels and GDM are causally related, GWAS data with an emphasis on women of reproductive age and other ethnic groups are required.

Exploring Candidate Gene Studies and Alexithymia: A Systematic Review.

Alexithymia is a trait involving difficulties in processing emotions. Genetic association studies have investigated candidate genes involved in alexithymia's pathogenesis. Therefore, the aim of the present study was to perform a systematic review of the genetic background associated with alexithymia. A systematic review of genetic studies of people with alexithymia was conducted. Electronic databases including PubMed, Scopus, and Web of Science were searched for the study purpose. We used the words "Alexithymia", "gene", "genetics", "variants", and "biomarkers". The present systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We found only candidate gene studies. A total of seventeen studies met the eligibility criteria, which comprised 22,361 individuals. The candidate genes associated with alexithymia were the serotoninergic pathway genes solute carrier family 6 member 4 (SLC6A4), serotonin 1A receptor (HTR1A), and serotonin 1A receptor (HTR2A); the neurotransmitter metabolism genes dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1), catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and oxytocin receptor (OXTR); and other pathway genes, vitamin D-binding protein (VDBP), tumor protein P53 regulated apoptosis inducing protein 1 (TP53AIP1), Rho GTPase Activating Protein 32 (ARHGAP32), and transmembrane protein 88B (TMEM88B). The results of this study showed that only case-control gene studies have been performed in alexithymia. On the basis of our findings, the majority of alexithymia genes and polymorphisms in this study belong to the serotoninergic pathway and neurotransmitter metabolism genes. These data suggest a role of serotoninergic neurotransmission in alexithymia. Nevertheless, more and future research is required to learn about the role of these genes in alexithymia.

Target trial emulation of preconception serum vitamin D status on fertility outcomes: a couples-based approach

To evaluate associations between preconception 25-hydroxyvitamin D (25(OH)D) levels and biomarkers in female and male partners on live birth (LB), pregnancy loss, and semen quality. Secondary analysis using the folic acid and zinc supplementation trial of couples seeking infertility treatment at four US centers (2013-2017). A target trial emulation framework was applied to estimate associations. Couples were observed for 9 months or through pregnancy. Clinics that provide reproductive endocrinology and infertility care in the US. Couples seeking infertility treatment. Preconception concentrations of 25(OH)D (primary) and associated biomarkers: vitamin D binding protein, calcium, free vitamin D, bioavailable vitamin D. Live birth and pregnancy loss were ascertained via self-report and medical records. Semen quality was ascertained 6 months after enrollment. Log-binomial regression estimated risk ratios and 95% confidence intervals (CIs). Individual and joint models and effect measure modification by preconception body mass index were considered. Among 2,370 couples, 19.5% of females and 29.9% of males were 25(OH)D deficient. Females with sufficient status had a 28%-higher likelihood of LB than deficient females (95% CI, 1.05-1.56). Female and male 25(OH)D status were associated with LB among those with normal body mass index (sufficient vs. deficient: female adjusted risk ratio [aRR], 1.39; 95% CI, 1.00-1.99; male aRR, 1.51; 95% CI, 1.01-2.25) and among obese female partners (sufficient vs. deficient: aRR, 1.33; 95% CI, 0.95-1.85). Couples whose both partners had higher 25(OH)D status had increased likelihood of LB (both not deficient vs. both deficient aRR, 1.26; 95% CI, 1.00-1.58). No associations were observed with pregnancy loss or semen quality. Similar results were found for all biomarkers except calcium. Preconception vitamin D status and bioavailability impact fertility among couples seeking infertility therapy, likely unrelated to semen quality. Body mass index stratified analyses demonstrated heterogeneous associations. NCT01857310.

Association of rs4588 polymorphism in vitamin D binding protein gene with polycystic ovarian syndrome in Iranian women: a case-control study

ObjectiveVitamin D deficiency and variations in the vitamin D binding protein (VDBP) gene may play a role in the development of Polycystic ovary syndrome (PCOS). This study aims to investigate the association of the rs4588 polymorphism with PCOS in Iranian women, as well as its association with infertility and recurrent pregnancy loss (RPL) in these patients.ResultsThe analysis revealed statistically significant differences in the distributions of genotypes and alleles of the rs4588 polymorphism among the three groups (p < 0.0001). The AC genotype and A allele showed an association with an elevated risk of PCOS and infertility. In this study, no association was found between genotypes and alleles of the rs4588 polymorphism and the risk of RPL in women with PCOS. Subjects with the AA or AC genotype exhibited significantly higher levels of LDL compared to those with the CC genotype.