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Vitamin D/VDR in the pathogenesis of intervertebral disc degeneration: Does autophagy play a role?
Lan, T, Shen, Z, Hu, Z, Yan, B
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112739
Abstract
To date, the underlying mechanisms involved intervertebral disc degeneration (IDD) remain unclear, which has hindered the development of molecular biological therapy for IDD. Autophagy is vital for intracellular quality control and metabolic balance in intervertebral disc cells. Hence, autophagy homeostasis is important. Emerging evidence has implicated vitamin D (VD) and the vitamin D receptor (VDR) in IDD progression because of their effects on different autophagy steps. However, the results of clinical trials in which VD supplementation was assessed as a treatment for IDD are controversial. Furthermore, experimental studies on the interplay between VD/VDR and autophagy are still in their infancy. In view of the significance of the crosstalk between VD/VDR and autophagy components, this review focuses on the latest research on VD/VDR modulation in autophagy and investigates the possible regulatory mechanisms. This article will deepen our understanding of the relationship between VD/VDR and autophagy and suggests novel strategies for IDD prevention and treatment.
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Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism.
Shigematsu, T, Asada, S, Endo, Y, Kawata, T, Fukagawa, M, Akizawa, T
PloS one. 2022;(2):e0262829
Abstract
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 μg], and high [≥ 1.5 μg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
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Polymorphisms Contributing to Calcium Status: A Systematic Review.
da Silva Lopes, K, Abe, SK
Nutrients. 2021;(8)
Abstract
This systematic review assessed genotypes and changes in calcium homeostasis. A literature search was performed in EMBASE, Medline and CENTRAL on 7 August 2020 identifying 1012 references. Studies were included with any human population related to the topic of interest, and genetic variations in genes related to calcium metabolism were considered. Two reviewers independently screened references, extracted relevant data and assessed study quality using the Q-Genie tool. Forty-one studies investigating Single Nucleotide Polymorphisms (SNPs) in relation to calcium status were identified. Almost half of the included studies were of good study quality according to the Q-Genie tool. Seventeen studies were cross-sectional, 14 case-control, seven association and three were Mendelian randomization studies. Included studies were conducted in over 18 countries. Participants were mainly adults, while six studies included children and adolescents. Ethnicity was described in 31 studies and half of these included Caucasian participants. Twenty-six independent studies examined the association between calcium and polymorphism in the calcium-sensing receptor (CASR) gene. Five studies assessed the association between polymorphisms of the Vitamin D receptor (VDR) gene and changes in calcium levels or renal excretion. The remaining ten studies investigated calcium homeostasis and other gene polymorphisms such as the CYP24A1 SNP or CLDN14. This study identified several CASR, VDR and other gene SNPs associated with calcium status. However, to provide evidence to guide dietary recommendations, further research is needed to explore the association between common polymorphisms and calcium requirements.
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Association between Polymorphisms in Vitamin D Pathway-Related Genes, Vitamin D Status, Muscle Mass and Function: A Systematic Review.
Krasniqi, E, Boshnjaku, A, Wagner, KH, Wessner, B
Nutrients. 2021;(9)
Abstract
An association between vitamin D level and muscle-related traits has been frequently reported. Vitamin D level is dependent on various factors such as sunlight exposure and nutrition. But also on genetic factors. We, therefore, hypothesize that single nucleotide polymorphisms (SNPs) within the vitamin D pathway-related genes could contribute to muscle mass and function via an impact on vitamin D level. However, the integration of studies investigating these issues is still missing. Therefore, this review aimed to systematically identify and summarize the available evidence on the association between SNPs within vitamin D pathway-related genes and vitamin D status as well as various muscle traits in healthy adults. The review has been registered on PROSPERO and was conducted following PRISMA guidelines. In total, 77 studies investigating 497 SNPs in 13 different genes were included, with significant associations being reported for 59 different SNPs. Variations in GC, CYP2R1, VDR, and CYP24A1 genes were reported most frequently, whereby especially SNPs in the GC (rs2282679, rs4588, rs1155563, rs7041) and CYP2R1 genes (rs10741657, rs10766197, rs2060793) were confirmed to be associated with vitamin D level in more than 50% of the respective studies. Various muscle traits have been investigated only in relation to four different vitamin D receptor (VDR) polymorphisms (rs7975232, rs2228570, rs1544410, and rs731236). Interestingly, all of them showed only very low confirmation rates (6-17% of the studies). In conclusion, this systematic review presents one of the most comprehensive updates of the association of SNPs in vitamin D pathway-related genes with vitamin D status and muscle traits in healthy adults. It might be used for selecting candidate SNPs for further studies, but also for personalized strategies in identifying individuals at risk for vitamin D deficiency and eventually for determining a potential response to vitamin D supplementation.
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Correlations among Pulmonary DJ-1, VDR and Nrf-2 in patients with Chronic Obstructive Pulmonary Disease: A Case-control Study.
Xiang, Y, Fu, L, Xiang, HX, Zheng, L, Tan, ZX, Wang, LX, Cao, W, Xu, DX, Zhao, H
International journal of medical sciences. 2021;(11):2449-2456
Abstract
Parkinson protein 7 (PARK7)/DJ-1 (DJ-1) is a redox sensitive molecular and stabilizer of nuclear factor erythroid 2-related factor 2 (Nrf-2). Nrf-2 regulates the downstream antioxidant defense system and exerts a significant function in patients with chronic obstructive pulmonary disease (COPD). Vitamin D receptor (VDR) is the nuclear receptor that regulates the downstream target genes. This study aimed to analyze the associations among pulmonary function, DJ-1, VDR and Nrf-2 in COPD patients. Serum was collected from 180 COPD patients and control subjects. Thirty-five lung tissues were obtained. DJ-1 was measured using ELISA and western blotting. Nrf-2 and VDR were detected by immunohistochemistry. Serum and pulmonary DJ-1 levels were lower in COPD patients than those in control subjects. Pulmonary VDR-positive nuclei were reduced in COPD patients. Nrf-2-positive nuclei were reduced in lung tissues of COPD patients. On the contrary, Nrf-2-related downstream target proteins were elevated in COPD patients. Further correlation analysis indicated that forced expiratory volume in 1 second (FEV1) was positively associated with pulmonary DJ-1, VDR and Nrf-2 in patients with COPD. In addition, there were positive correlations among DJ-1, VDR and Nrf-2 in lung tissues of COPD patients. In conclusion, DJ-1, VDR and Nrf-2 were decreased in COPD patients compared with control subjects. The reduction of DJ-1 and VDR associating with Nrf-2 downregulation may be involved in the process of COPD.
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Vitamin D Receptor Gene Single Nucleotide Polymorphisms and Association With Vitamin D Levels and Endoscopic Disease Activity in Inflammatory Bowel Disease Patients: A Pilot Study.
Shirwaikar Thomas, A, Criss, ZK, Shroyer, NF, Abraham, BP
Inflammatory bowel diseases. 2021;(8):1263-1269
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Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) comprise a heterogenous group of chronic gastrointestinal disorders that are multifactorial in etiology. Experimental in vitro and in vivo studies suggest that intestinal vitamin D receptor (VDR) signaling plays a role in modulating the immune response in IBD as a cause and/or a consequence of chronic inflammation. AIM: The aim of this study is to study the associations between vitamin D receptor gene single nucleotide polymorphisms(SNPs), vitamin D levels, and endoscopic disease activity in IBD. METHODS This is a cross-sectional analysis of IBD patients who underwent endoscopic evaluation at a tertiary care hospital. Demographic variables, IBD disease type and location, medical therapies, vitamin D levels, and endoscopic disease activity were collected. Colonic biopsies obtained were investigated for the presence of VDR SNPs: ApaI, TaqI, BsmI, FokI, and Tru9I. RESULTS Patients in endoscopic remission had higher vitamin D levels compared with those with inflammation found on endoscopy (P = <0.001). Patients with lower vitamin D levels were homozygous for Fok ancestral alleles (P = 0.0045). With regard to endoscopic disease activity, we found no differences in mutations of any of the VDR SNPs in our sample. CONCLUSIONS The association between the presence of the ancestral FokI and lower vitamin D levels suggests a multifactorial etiology for vitamin D deficiency in IBD. Higher vitamin D levels in those in endoscopic remission compared with lower levels in those with active inflammation suggests that the impact of VDR gene SNP on disease activity may be overcome with replacement therapy.
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Growth, Dietary Intake, and Vitamin D Receptor (VDR) Promoter Genotype in Indonesian School-Age Children.
Angelin, TC, Bardosono, S, Shinta, D, Fahmida, U
Nutrients. 2021;(9)
Abstract
Nutrition has been known as a predominant factor associated with stunting. However, some studies have discovered a genetic contribution in calcium absorption that will affect growth, known as the VDR gene. The aim of this study was to assess the association between VDR gene polymorphism and dietary intake towards height-for-age z-score (HAZ) of elementary school children in Malang District, East Java. This study analyzed the baseline of a randomized trial in East Java, Indonesia. School children aged 8-10 years old (n = 142) were included in this study. Energy, protein, calcium, and vitamin D intakes were obtained using 4-day 24-h dietary recalls. Two SNPs located in the promoter region of VDR gene were selected (rs11568820 and rs4516035) and analyzed using Real-Time PCR. The result showed a significant correlation between energy and protein intake with HAZ of the children (p = 0.030 and p = 0.016, respectively). The association between VDR gene and HAZ was not found (p > 0.05). Adjusted by other factors, protein intake was significantly correlated with HAZ (β = 0.034, 95% CI 0.015-0.052, p < 0.001, adj. R2 = 0.089). The children in our study had a favorable VDR gene genotype, however the effect of VDR gene promoter activity might not be revealed due to very low vitamin D and calcium intake to stimulate intestinal calcium absorption which in turn affects HAZ.
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Vitamin D receptor gene polymorphisms and risk of intervertebral disc degeneration: An updated meta-analysis based on 23 studies.
Xue, J, Song, Y, Liu, H, Liu, L, Li, T, Gong, Q
Medicine. 2021;(20):e25922
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Abstract
BACKGROUND Numerous studies have investigated the associations between Vitamin D receptor (VDR) gene polymorphisms and risk of intervertebral disc degeneration but the results remain controversial. This study aimed to drive a more precise estimation of association between VDR gene polymorphisms and risk of intervertebral disc degeneration. METHODS PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated Database for papers on VDR gene polymorphisms and risk of intervertebral disc degeneration were searched. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive model. RESULTS Overall, 23 articles were included in the final meta-analysis. The subgroup analyses by ethnicity showed a significant association of VDR FokI mutation with disc degeneration risk in Caucasians (recessive model, OR with 95%CI 1.301, [1.041, 1.626]; additive model, OR with 95%CI 1.119, [1.006, 1.245]). The results of subgroup analyses by ethnicity showed a significant association of VDR TaqI mutation with disc degeneration risk in Asians but not in Caucasians. There was a significant association between VDR ApaI mutation and risk of disc degeneration and subgroup analyses by ethnicity showed a significant association in Caucasians and in Asians. CONCLUSIONS In summary, VDR FokI polymorphisms was associated with disc degeneration risk among Caucasians but not Asians, VDR TaqI polymorphisms was associated with disc degeneration risk among Asians but not Caucasians, while VDR ApaI polymorphism was associated with disc degeneration risk among Asians and Caucasians.
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Vitamin D Receptor and Vitamin D Binding Protein Gene Polymorphisms Are Associated with Renal Allograft Outcome.
Zununi Vahed, S, Ahmadian, E, Foroughi, P, Mostafavi, S, Madry, H, Ardalan, M, Cucchiarini, M
Nutrients. 2021;(4)
Abstract
Vitamin D deficiency has adverse effects on renal allograft outcomes, and polymorphisms of genes encoding vitamin D-binding protein (VDBP) and vitamin D receptor (VDR) are defined to play a role in these conditions. The goal of the current investigation was to evaluate the connection between those polymorphisms with acute rejection, viral infection history, and recipients' vitamin D status. In this study, 115 kidney transplant recipients and 100 healthy individuals were included. VDR polymorphisms including FokI (rs2228570), Apal (rs7975232), BsmI (rs1544410), as well as VDBP (rs7040) polymorphisms were studied using high resolution melting (PCR-HRM) analysis among the studied groups. The frequency of G allele in Apal rs7975232 polymorphism in the kidney transplant recipients was 0.63 times lower than healthy individuals (p = 0.026). Further, the G allele frequency in VDBP rs7040 polymorphism was significantly lower in patients with allograft rejection (p = 0.002). Considering the incidence of viral infection, significant differences were identified between the frequencies of VDR FokI (OR = 2.035; 95% CI 1.06-2.89, p = 0.030) and VDBP rs7040 (OR = 0.40; 95% CI 0.24-0.67, p < 0.001) T alleles in the studied groups. Moreover, the VDBP rs7040 GG genotype distribution was low in the recipients with a history of viral infection (p = 0.004). VDR (FokI) and VDBP (rs7040) alleles and their genotype distribution are significantly associated with allograft outcomes including allograft rejection and viral infection in the studied population.
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Study of vitamin D receptor gene polymorphisms in a cohort of myocardial infarction patients with coronary artery disease.
Raljević, D, Peršić, V, Markova-Car, E, Cindrić, L, Miškulin, R, Žuvić, M, Kraljević Pavelić, S
BMC cardiovascular disorders. 2021;(1):188
Abstract
BACKGROUND Vitamin D deficiency is associated with cardiovascular diseases, including coronary artery diseases (CAD). As vitamin D manifests its biological function through its vitamin D receptor (VDR), VDR gene polymorphisms potentially affect VDR functionality and vitamin D activity. Therefore, the objective of this study was to analyze three well-studied VDR gene polymorphisms-Fok1 (rs2228570), BsmI (rs1544410) and Taq1 (rs731236)-in a cohort of CAD patients after acute myocardial infarction. METHODS In the presented cross-sectional study, 155 participants with CAD after acute myocardial infarction and 104 participants in a control group without CAD were enrolled. The participants in both groups were Caucasians of European origin. The genotyping of VDR polymorphisms rs2228570, rs1544410 and rs731236 was assessed by RT-PCR. RESULTS The results show an association between the T/T genotype of the BsmI (rs1544410) and the G/G genotype of the Taq1 (rs731236) VDR polymorphism and CAD patients after acute myocardial infarction. There was no association between the Fok1 (rs2228570) VDR polymorphism and CAD patients after acute myocardial infarction. CONCLUSION The presented results suggest a potential association of the BsmI (rs1544410) and Taq1 (rs731236) VDR polymorphisms with CAD patients after myocardial infarction.