Astragalus Polysaccharide Mediates Immunomodulatory Effects on Crosstalk between Human Peripheral Blood Mononuclear Cells and Ovarian Cancer Cell Line.

Astragalus polysaccharide (APS) is a functional component of Astragalus membranaceus with antitumor and immunomodulatory properties. This study evaluated the effect of APS on the peripheral blood mononuclear cell (PBMC) proliferation, cytokine secretion, and regulatory T cell (Treg) induction in an in vitro coculture model of human PBMCs and A2780 human ovarian cancer cells. PBMC proliferation and Treg frequency were measured by flow cytometry. Cytokine levels were assessed by enzyme-linked immunosorbent assay. APS significantly enhanced the PBMC proliferation, reduced Treg frequency, decreased anti-inflammatory cytokines including interleukin [IL]-10, transforming growth factor beta (TGF-ß), and vascular endothelial growth factor-A (VEGF-A), and increased the pro-inflammatory cytokine IL-6. These findings suggest that APS may be an effective immunomodulatory supplement for cancer therapy, particularly for ovarian cancer by enhancing antitumor immune responses.

Exosomes from Adipose Tissue-derived Mesenchymal Stem Cells Induce Regulatory T Cells in COVID-19 Patients.

An imbalance between regulatory T (Treg) and T-helper (Th)-17 cells has been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) exert immunomodulatory properties through secreting exosomes. This study aimed to assess the effect of MSC-derived exosomes (MSC-Exo) on the differentiation of peripheral blood mononuclear cells (PBMCs) into  Tregs from patients with COVID-19. Exosomes were isolated from adipose tissue-derived MSCs. PBMCs were separated from the whole blood of COVID-19 patients (n=20). Treg frequency was assessed before and 48 hours after treatment of PBMCs with MSC-Exo using flow cytometry. Expression of FOXP3 and cytokine genes, and the concentration of cytokines associated with Tregs, were assessed before and after treatment with MSC-Exo. The frequency of CD4+CD25+CD127-  Tregs was significantly higher after treating PBMCs with MSC-Exo (6.695±2.528) compared to before treatment (4.981±2.068). The expressions of transforming growth factor (TGF)-ß1, interleukin (IL)-10, and FOXP3 were significantly upregulated in MSC-Exo-treated PBMCs. The concentration of IL-10 increased significantly after treatment (994.7±543.9 pg/mL) of PBMCs with MSC-Exo compared with before treatment (563.5±408.6 pg/mL). The concentration of TGF-ß was significantly higher in the supernatant of PBMCs after treatment with MSC-Exo (477.0±391.1 pg/mL) than PBMCs before treatment (257.7±226.3 pg/mL). MSC-Exo has the potential to raise anti-inflammatory responses by induction of  Tregs, potentiating its therapeutic effects in COVID-19.

Comparison of OX40 expression in patients with multiple sclerosis and neuromyelitis optica as an approach to diagnosis.

BACKGROUND: Previous studies have shown that CD134 (OX40) co-stimulation is involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) models and the antigen is expressed within multiple sclerosis lesions in humans. OX40 (CD134) is thought to be a secondary co-stimulatory immune checkpoint molecule that is expressed by T cells. This study aimed to evaluate the mRNA expression of OX40 and its serum levels in the peripheral blood of patients with Multiple Sclerosis (MS) or Neuromyelitis Optica (NMO). METHODS: Patients with MS (n = 60), NMO (n = 20), and 20 healthy subjects were recruited from Sina Hospital, Tehran, Iran. The diagnoses were confirmed by a specialist in clinical neurology. Peripheral venous blood was obtained from all subjects, and mRNA quantification of OX40 was conducted using real-time PCR. Serum samples were also obtained and the concentration of OX40 was determined using an enzyme-linked immunosorbent assay (ELISA). RESULTS: There was a significant correlation between the mRNA expression and serum levels of OX40 and disability as assessed using the expanded disability status scale (EDSS) in the patients with MS, but not in the patients with NMO. Expression of OX40 mRNA was significantly higher in the peripheral blood of MS patients compared to healthy individuals and NMO patients (*P < 0.05). In addition, serum OX40 concentrations were also significantly higher in patients with MS patients compared with healthy subjects (9.08 ± 2.48 vs. 1.49 ± 0.54 ng/ml; P = 0.041). CONCLUSIONS: It appears that an increased expression of OX40 may be associated with the hyperactivation of T cells in patients with MS, and this may play a role in the pathogenesis of the disease.

Potential therapeutic applications of extracellular vesicles in the immunopathogenesis of COVID-19.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) which has emerged as a global health crisis. Recently, more than 50 different types of potential COVID-19 vaccines have been developed to elicit a strong immune response against SARS-CoV-2. However, genetic mutations give rise to the new variants of SARS-CoV-2 which is highly associated with the reduced effectiveness of COVID-19 vaccines. There is still no efficient antiviral agent to specifically target the SARS-CoV-2 infection and treatment of COVID-19. Therefore, understanding the molecular mechanisms underlying the pathogenesis of SARS-CoV-2 may contribute to discovering a novel potential therapeutic approach to the management of COVID-19. Recently, extracellular vesicle (EV)-based therapeutic strategies have received great attention on account of their potential benefits in the administration of viral diseases. EVs are extracellular vesicles containing specific biomolecules which play an important role in cell-to-cell communications. It has been revealed that EVs are involved in the pathogenesis of different inflammatory diseases such as cancer and viral infections. EVs are released from virus-infected cells which could mediate the interaction of infected and uninfected host cells. Hence, these extracellular nanoparticles have been considered a novel approach for drug delivery to mediate the treatment of a wide range of diseases including, COVID-19. EVs are considered a cell-free therapeutic strategy that could ameliorate the cytokine storm and its complications in COVID-19 patients. Furthermore, EV-based cargo delivery such as immunomodulatory agents in combination with antiviral drugs may have therapeutic benefits in patients with SARS-CoV-2 infection. In this review, we will highlight the potential of EVs as a therapeutic candidate in the diagnosis and treatment of COVID-19. Also, we will discuss the future perspectives regarding the beneficial effects of Evs in the development of COVID-19 vaccines.

Role of NKT cells in cancer immunotherapy-from bench to bed.

Natural killer T (NKT) cells are a specific T cell subset known to express the αß-T cell receptor (TCR) for antigens identification and express typical NK cell specifications, such as surface expression of CD56 and CD16 markers as well as production of granzyme. Human NKT cells are divided into two subgroups based on their cytokine receptor and TCR repertoire. Both of them are CD1-restricted and recognize lipid antigens presented by CD1d molecules. Studies have demonstrated that these cells are essential in defense against malignancies. These cells secret proinflammatory and regulatory cytokines that stimulate or suppress immune system responses. In several murine tumor models, activation of type I NKT cells induces tumor rejection and inhibits metastasis's spread. However, type II NKT cells are associated with an inhibitory and regulatory function during tumor immune responses. Variant NKT cells may suppress tumor immunity via different mechanisms that require cross-talk with other immune-regulatory cells. NKT-like cells display high tumor-killing abilities against many tumor cells. In the recent decade, different studies have been performed based on the application of NKT-based immunotherapy for cancer therapy. Moreover, manipulation of NKT cells through administering autologous dendritic cell (DC) loaded with α-galactosylceramide (α-GalCer) and direct α-GalCer injection has also been tested. In this review, we described different subtypes of NKT cells, their function in the anti-tumor immune responses, and the application of NKT cells in cancer immunotherapy from bench to bed.

Evaluation of effective factors on IL-10 signaling in B cells in patients with selective IgA deficiency

Background: Selective IgA deficiency is the most prevalent form of primary immunodeficiencies. The pathogenesis of the disease is still unknown. Several studies have suggested a defect in B cell responses to IL-10; however, the main reason for this defect has not been reported. Elucidating IL-10 signaling defects and their correlation with clinical manifestations could be helpful for better understanding and treatment of the disease. Methods: In this study, 15 SIgAD patients and 15 age- and sex-matched healthy controls were included. Surface expression of transforming growth factor ß receptor II (TGF-ß RII), IL-10R and IgA was assessed by flow cytometry in human purified B cells before and after stimulation by IL-10. Protein expression of STAT3, p-STAT3 and SOCS3 was measured by Western blotting analysis. TGF-ß and IgA secretion was evaluated by ELISA. Finally, the measurement of B cell apoptosis was performed by flow cytometry. Results: The TGF-ßRII expression level was decreased after stimulation with IL-10 in patients compared with controls. Notably, the TGF-ß level were higher after stimulation with mCD40L and IL-10 in the control group as compared to stimulation with mCD40L alone. The IgA+ B cell percentage and IgA secretion levels were significantly increased in controls as compared with SIgAD patients. The relative concentration of the total STAT3 was decreased as compared with controls. Conclusion: The defect in IgA production in SIgAD patients could be due to inadequate B cell responses to IL-10 stimulation that probably originate from defective regulation of IL-10-mediated TGF-b 'symbol' production TGF-ß response by IL-10. Furthermore, it is suggested that the absence of STAT3 protein baseline expression could impair cytokine-mediated signaling such as thatinduced by IL-!0 and IL-21.

Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update.

During pregnancy, complicated connections are formed between a mother and a fetus. In a successful pregnancy, the maternal-fetal interface is affected by dynamic changes, and the fetus is protected against the mother's immune system. Natural killer (NK) cells are one of the immune system cells in the female reproductive system that play an essential role in the physiology of pregnancy. NK cells not only exist in peripheral blood (PB) but also can exist in the decidua. Studies have suggested multiple roles for these cells, including decidualization, control of trophoblast growth and invasion, embryo acceptance and maintenance by the mother, and facilitation of placental development during pregnancy. Natural killer T (NKT) cells are another group of NK cells that play a crucial role in the maintenance of pregnancy and regulation of the immune system during pregnancy. Studies show that NK and NKT cells are not only effective in maintaining pregnancy but also can be involved in infertility-related diseases. This review focuses on NK and NKT cells biology and provides a detailed description of the functions of these cells in implantation, placentation, and immune tolerance during pregnancy and their role in pregnancy complications.

Anti-Caspr-conjugated gold nanoparticles emergence as a novel approach in the treatment of EAE animal model.

Multiple sclerosis (MS) is a chronic autoimmune disorder of central nervous system which is increasing worldwide. Although immunosuppressive agents are used for the treatment of MS disease, nevertheless the lack of non-toxic and efficient therapeutic method is perceptible. Hence, this study aims to evaluate the effect of Contactin-associated protein (Caspr) antibody-, poly ethylene glycol (PEG)- and exosome combined gold nanoparticles (GNPs) in comparison to Glatiramer acetate as a selective treatment of MS disease in the experimental autoimmune encephalomyelitis (EAE) mouse model. EAE was induced in female C57BL/6 mice and 25-day treatment with anti-Caspr-, PEG- and exosome combined GNPs was evaluated. Histopathological examination of spinal cord, regulatory T cells as well as inflammatory pathway including IFN-É£ and IL-17 and mir-326 were investigated. The results showed the severity of MS symptoms was significantly decreased in all treated groups. Histological examination of the spinal cord indicated the reduced demyelination and immune cell infiltration. Besides, regulatory T cells were significantly increased following all treatments. Remarkably, the cytokine levels of IFN-É£ and IL-17 as well as mir-326 is altered in treated groups. Taken together, the obtained findings demonstrate that the administration of anti-Caspr-, PEG- and exosome combined GNPs can be considered a potential treatment in MS disease.

Plasminogen Activator Inhibitor-1 Polymorphisms and Risk of Coronary Artery Disease: Evidence From Meta-Analysis and Trial Sequential Analysis.

A systematic review and meta-analysis were conducted to find out if there was association between Plasminogen Activator Inhibitor-1 (PAI-1) gene polymorphisms (- 844 G > A and - 675 4G > 5G) and susceptibility to coronary artery disease (CAD). Search of electronic databases was performed and the pooled odds ratio (OR) and 95% confidence interval (CI) were exerted to evaluate the pooled association between the single-nucleotide polymorphisms (SNPs) and risk of CAD. For - 675 4G > 5G SNP, dominant (OR = 0.90), recessive (OR = 0.90), allelic (OR = 0.91), homozygous (OR = 0.84), and heterozygous (OR = 0.96) models were significantly associated with decreased risk of CAD. Moreover, all five genetic models were associated significantly with decreased CAD risk in the Causation and Arab populations. The results in Asians were marginally significant in recessive, allelic, and homozygote models. The male gender was found to be a risk factor in individuals with PAI-1 4G > 5G SNP in the dominant model (OR = 0.89), recessive model (OR = 0.91), allelic model (OR = 0.92), homozygous model (OR = 0.86), and heterozygous model (OR = 0.91). The results of pooled ORs for overall populations and subgroup analysis by ethnicity reject any association between PAI-1 gene - 844 G > A polymorphism and CAD risk under all genetic comparisons. The results of this meta-analysis indicated that PAI-1 4G > 5G SNP was associated with decreased risk of CAD in the overall population as well as in the Asians, Caucasians, and Arab populations. However, the PAI-1 gene - 844 G > A polymorphism had no significant association with susceptibility to CAD.

Placental Extract and Exosomes Derived from Pregnant Mice Attenuate the Development of Experimental Autoimmune Encephalomyelitis.

Placental extract (PE) and exosomes from pregnant mice appear to have immunomodulatory and neuroprotective effects. In this study, we assessed the potential therapeutic effects of PE and exosomes obtained from pregnant mice in experimental autoimmune encephalomyelitis (EAE) mouse models. C57BL/6 mice, 8 to 12 weeks of age, were prepared and administered PE, exosomes, and glatiramer acetate (GA), as an FDA-approved treatment for multiple sclerosis (MS), after EAE induction. Thereafter, the therapeutic effects of treatment were evaluated by measuring the clinical courses of the mice as well as determining the number of regulatory T (Treg) cells using flow cytometry, cytokine levels, and microRNA-326 expression via real-time PCR. GA, PE, and exosomes reduced clinical severity, the extent of spinal cord demyelination, and the infiltration of inflammatory cells into the spinal cord. The frequency of CD4+CD25+FoxP3+ Treg cells increased after treatment of EAE mice with GA, PE, and exosomes. The mRNA expression of the inflammatory cytokines (interleukin-17  and interferon-gamma), as well as miR-326 expression, decreased significantly in the EAE mice after treatment with GA and exosomes. PE and exosomes from pregnant mice are involved in the modulation of Treg/Th17 balance and provide a therapeutic approach for MS. Further clinical studies will hopefully confirm the safety and efficacy of such treatments in MS patients.

Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight.

The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.

Implications the Role of miR-155 in the Pathogenesis of Autoimmune Diseases.

MicroRNAs (miRNAs) are small noncoding conserved RNAs containing 19 to 24 nucleotides that are regulators of post-translational modifications and are involved in the majority of biological processes such as immune homeostasis, T helper cell differentiation, central and peripheral tolerance, and immune cell development. Autoimmune diseases are characterized by immune system dysregulation, which ultimately leads to destructive responses to self-antigens. A large body of literature suggests that autoimmune diseases and immune dysregulation are associated with different miRNA expression changes in the target cells and tissues of adaptive or innate immunity. miR-155 is identified as a critical modulator of immune responses. Recently conducted studies on the expression profile of miR-155 suggest that the altered expression and function of miR-155 can mediate vulnerability to autoimmune diseases and cause significant dysfunction of the immune system.

Immune checkpoints and cancer development: Therapeutic implications and future directions.

Over the past few decades, different inhibitory receptors have been identified, which have played prominent roles in reducing anti-tumor immune responses. The role of immune checkpoint inhibitors in cancer was revealed by critical blockade of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) checkpoints. Immune checkpoint inhibitors, including anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (Atezolizumab, avelumab, and duravulumab), and anti-CTLA-4 (ipilimumab, tremelimumab), are currently FDA-approved treatment options for a broad range of cancer types. However, regarding immunotherapy advances in recent years, most studies have been focused on finding the antibodies against other inhibitory immune checkpoints in the tumor microenvironment such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin, and mucin domain 3 (TIM-3), B7-homolog 3 (B7-H3), V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA), diacylglycerol kinase-α (DGK-α), T cell immunoglobulin and ITIM domain (TIGIT), and B and T lymphocyte attenuator (BTLA). This immune checkpoint exerts differential inhibitory impacts on various types of lymphocytes. The suppression of immune responses demonstrates a surprising synergy with PD-1. Therefore, most antibodies against these immune checkpoints are undertaking clinical trials for cancer immunotherapy of advanced solid tumors and hematologic malignancies. In this review, we will summarize recent findings of immune checkpoint and the role of monoclonal antibodies in cancer immunotherapy targeting these receptors.

Interleukin-10 Gene Promoter Polymorphisms and Susceptibility to Asthma: Systematic Review and Meta-analysis.

Several studies have previously assessed the association between interleukin (IL)-10 gene polymorphisms and the risk of asthma, leading to conflicting results. To resolve the incongruent outcomes yielded from different single studies, we conducted the most up-to-date meta-analysis of the IL-10 gene rs1800896, rs1800871, and rs1800872 single-nucleotide polymorphisms (SNPs) and susceptibility to asthma. A systematic literature search performed until April 2020, and the pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were calculated to determine the association strength. Thirty articles comprising 5678 asthmatic patients and 6079 controls met the inclusion criteria. No significant association was found between rs1800872 SNP and susceptibility to asthma across all genetic models in the overall and subgroup analyses. The rs1800871 SNP had only significant association with a decreased risk of asthma in Europeans (OR 0.66, CI 0.53-0.82, P < 0.001). However, rs1800896 SNP was significantly associated with a decreased risk of asthma by dominant (OR 0.67, CI 0.50-0.90, P < 0.001) and heterozygote (OR 0.66, CI 0.49-0.88, P < 0.001) models in the overall analysis. Subgroup analyses indicated significant association of rs1800896 SNP by dominant (OR 0.45, CI 0.28-0.72, P < 0.001) and heterozygote (OR 0.43, CI 0.26-0.70, P < 0.001) models in the African population. The IL-10 rs1800896 SNP confers protection against the risk of asthma, especially in Africans. Additionally, rs1800871 SNP has a protective role against asthma in Europeans.

Vitamin D Receptor (VDR) Gene Polymorphisms and Risk of Coronary Artery Disease (CAD): Systematic Review and Meta-analysis.

Several studies have noted that vitamin D receptor (VDR) gene polymorphisms are involved in the susceptibility to Coronary artery disease (CAD). Nonetheless, the results have been inconclusive. Here, we performed the most up-to-date analysis of the association between VDR gene polymorphisms and risk of CAD. We conducted a comprehensive systematic search in the major electronic database, including Scopus and PubMed to look up for relevant studies evaluating the association between the VDR gene FokI (rs2228570), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms and susceptibility to CAD published before December 2019. The level of association between VDR gene polymorphisms and susceptibility to CAD in the polled analysis was calculated by odds ratio (OR) and the corresponding 95% confidence interval (CI). We found 14 articles containing 20,398 cases and 9371 controls. The analysis revealed that all genetic models in the FokI SNP were associated with increased risk of CAD. Furthermore, for the ApaI SNP, except recessive model, all other genetic models significantly increased the risk of CAD in the overall analysis. In addition, it was divulged that both FokI and ApaI SNPs were involved in increasing the risk of CAD in Asians and Europeans in a number of models. FokI and ApaI polymorphisms may confer a susceptibility genetic risk factor for development of CAD, particularly in the Asian population.

Systematic review and meta-analytic findings on the association between killer-cell immunoglobulin-like receptor genes and susceptibility to pulmonary tuberculosis.

Several studies have evaluated the association between killer-cell immunoglobulin-like receptors (KIR) genes and susceptibility risk to tuberculosis (TB) infection. Nonetheless, their outcomes have not been conclusive and consistent. Here we implemented a systematic review and meta-analysis of KIR genes association to susceptibility risk of pulmonary TB (PTB) infection to attain a clear understanding of the involvement of these genes in susceptibility to PTB infection. A systematic search was conducted in the MEDLINE/PubMed and Scopus databases to find case-control studies published before November 2020. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated to determine the association between KIR genes and risk of PTB infection. After comprehensive searching and implementing the inclusion and exclusion criteria, 10 case-control studies were included in the meta-analysis. Four KIR genes were found to have significant positive association with PTB susceptibility risk of infection, including 2DL3 (OR = 1.454, 95% CI = 1.157-1.827; P = 0.001), 2DS1 (OR = 1.481, 95% CI = 1.334-1.837; P < 0.001), 2DS4 (OR = 1.782, 95% CI = 1.273-2.495; P = 0.001) and 3DL1 (OR = 1.726, 95% CI = 1.277-2.333; P < 0.001). However, the results showed that the remaining KIR genes (2DS2-4, 2DL1, 2, 4, 3DL1-2) and two pseudogenes (2DP1 and 3DP1) did not have significant associations with risk of PTB infection. This meta-analysis provides reliable evidence that the KIR genes 2DL3, 2DS1, 2DS4, and 3DL1 may be associated with an increased risk of PTB infection.

Human placental extract attenuates neurological symptoms in the experimental autoimmune encephalomyelitis model of multiple sclerosis-a putative approach in MS disease?

BACKGROUND: Different studies have demonstrated the anti-inflammatory effects of human placental extract both in vivo and in vitro. Considering the chronic inflammatory nature of multiple sclerosis (MS) disease, we examined whether or not the administration of human placental extract is able to attenuate the neurological symptoms detected in experimental autoimmune encephalomyelitis (EAE) model of MS. METHODS: The injected myelin oligodendrocyte glycoprotein (MOG) induced EAE in mice, and treatment began from day 4 post-injection by intraperitoneal administration of 0.2 mg/kg human placental extract, repeated every other day up to day 31 post-injection. At the end of the treatment, luxol fast blue (LBS) staining and hematoxylin and eosin (H&E) staining were performed to evaluate the demyelination of neurons and inflammatory responses, respectively. Further assessed were the serum concentrations of IL-23 and IL-27. RESULTS: The administration of human placental extract was able to significantly reduce the mean clinical score in EAE mice, decrease the pro-inflammatory process and attenuate neural demyelination. Moreover, while the serum concentration of IL-23 was significantly diminished in the EAE mice receiving human placental extract compared to the non-treated EAE group, IL-27 concentration was significantly increased. CONCLUSIONS: Our findings demonstrated the administration of human placental extract could significantly attenuate the neurological symptoms in the EAE model of MS in part through modulating the serum levels of IL-23 and IL-27 and enhancing neuroprotection and myelin repair.

Vitamin D receptor gene polymorphisms and susceptibility to urolithiasis: a meta-regression and meta-analysis.

BACKGROUND: The currently available data with respect to the association between vitamin D receptor (VDR) gene polymorphism and risk to urolithiasis are inconclusive and inconsistent. Hence, an exhaustive meta-analysis can solve the discrepancies and provide a hint for upcoming investigations. Herein, a meta-analysis was carried out to attain a conclusive estimate of the association between VDR gene single nucleotide polymorphisms (SNPs) and urolithiasis risk. METHODS: The major databases, including ISI Web of science, Scopus, and PubMed/MEDLINE were searched systematically from until June 2020 to retrieve all relevant studies. Association between VDR gene polymorphisms, including FokI (rs2228570), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and urolithiasis risk was evaluated using pooled odds ratio (OR) and their corresponding 95% confidence interval (CI). Additionally, to seek for the potential source of heterogeneity, meta-regression analyses were exerted. RESULTS: Literature search led to finally finding of 33 studies evaluating the VDR gene SNPs and urolithiasis risk. It was observed that none of the four SNPs were significantly associated with urolithiasis predisposition. However, subgroup analysis confirmed higher risk of urolithiasis in East-Asian and Caucasian population with ApaI and TaqI gene polymorphism. The analyses of sensitivity acknowledged the results stability. CONCLUSION: Although this meta-analysis did not support the association of FokI, TaqI, BsmI, and ApaI in the overall polled analysis, it suggests that ApaI and TaqI SNPs is associated with increased risk of urolithiasis in East-Asian and Caucasians populations.