Alzheimer\'s disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer\'s disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer\'s disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer\'s disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer\'s disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer\'s disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer\'s disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer\'s disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

BACKGROUND: Evidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited.
OBJECTIVE: We aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association.
METHODS: This study included 19,851 participants with T2D from United Kingdom Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders.
RESULTS: In patients with T2D, the incidence rate of infections was 29.3/1000 person-y. Compared with those with 25(OH)D of 50.0-74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections, and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall < 0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall < 0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction > 0.050).
CONCLUSIONS: In patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.

OBJECTIVE: To evaluate the association between vitamin D receptor (VDRs) and calcium-sensitive receptor (CaSR) gene polymorphisms and calcium-containing kidney stones (CCKS) in Dai populations.
METHODS: A total of 160 CCKS patients and 87 healthy controls were included in this study. CCKS was confirmed using urological computed tomography (CT), plain abdominal radiograph, or surgical lithotomy. Stone samples obtained during surgery were analyzed using infrared spectroscopy. Venous blood and 24-h urine samples were collected and analyzed using Sanger sequencing and high-performance liquid chromatography, respectively. Genetic variants in the VDR gene (rs7975232, rs2228570, rs731236, and rs1544410) and CaSR gene (rs7652589, rs1801725, and rs1042636) were identified through sequence analysis.
RESULTS: Analysis of genotype and allele frequencies revealed that the rs7975232 polymorphism in the VDR gene and the rs7652589 allele in the CaSR gene were significantly associated with CCKS. Furthermore, patients carrying the AC and AA genotypes of rs7975232 showed a higher incidence of hypocitraturia compared to those with other genotypes (p < 0.05). The AA and GG genotypes of rs1042636 and the AA genotype of rs7652589 were significantly associated with hypercalciuria (p < 0.05).
CONCLUSIONS: CCKS in this study population may be closely related to hypocitraturia caused by the VDR locus rs7975232 polymorphism and hypercalciuria caused by the CaSR locus rs1042636 and rs7652589 polymorphism.

BACKGROUND: Diabetes mellitus is a chronic and multifactorial condition, including environmental risk factors such as lifestyle habits and genetic conditions.
OBJECTIVE: We aimed to evaluate the association of VDR gene polymorphism (rs2228570) FokI and vitamin D levels with diabetes in adults.
METHODS: Cross-sectional population-based study in adults, conducted from October to December 2020 in two Brazilian cities. The outcome variable was diabetes, defined as glycated hemoglobin ≥ 6.5% or self-report medical diagnosis or use of oral hypoglycemic drugs. Vitamin D (25-hydroxyvitamin D) was measured by indirect electrochemiluminescence, and classified as deficiency when 25(OH)D < 20 ng/mL. All participants were genotyped for VDR FokI polymorphism by qPCR and classified as homozygous mutant (ff or GG), heterozygous (Ff or AG), or homozygous wild (FF or AA). A combined analysis between the FokI polymorphism and vitamin D levels with diabetes was also examined. A directed acyclic graph (DAG) was used to select minimal and sufficient adjustment for confounding variables by the backdoor criterion.
RESULTS: The prevalence of DM was 9.4% and vitamin D deficiency (VDD) was 19.9%. The genotype distribution of FokI polymorphism was 9.9% FF, 44.8% Ff, and 45.3% ff. It was possible to verify a positive association between vitamin D deficiency and DM (OR = 2.19; 95% CI: 1.06-4.50). Individuals with the altered allele (ff) had a 1.78 higher prevalence of DM (OR: 1.78; 95% CI; 1.10-2.87). Combined analyses, individuals with vitamin D deficiency and one or two copies of the altered FokI allele had a higher prevalence of DM (Ff + ff: OR: 1.67; 95% CI; 1.07-2.61; ff: OR: 3.60; 95% CI; 1.40-9.25).
CONCLUSIONS: Our data suggest that vitamin D deficiency and FokI polymorphism are associated with DM.

The associations of vitamin D receptor (VDR)- single nucleotide polymorphisms (SNPs) with the symptoms of COVID-19 may vary between patients with different severities of COVID-19. Therefore, in the present study, we aim to compare VDR polymorphisms in severe and mild COVID-19 patients. In this study, a total number of 85 hospitalized patients and 91 mild/moderate patients with COVID-19 were recruited. SNPs in VDR genes were determined using ARMS and then confirmed by sanger sequencing. The mean (SD) age of participants in hospitalized and non-hospitalized group was 59.0 (12.4) and 47.8 (14.8) years, respectively. Almost 46% of participants in hospitalized and 48% of participant in non-hospitalized group were male. The frequency of TT genotype of SNP rs11568820 was significantly lower in hospitalized than non-hospitalized group (3.5% vs. 17.6%; P = 0.018). However, there was no significant differences between genotypes of SNPs rs7970314 and rs4334089 and also alleles frequencies in all SNPs of two groups. The genotype of rs11568820 SNP had an inverse association with hospitalization of patients with COVID-19 after adjustment for comorbidities [OR 0.18, 95% CI 0.04, 0.88; P = 0.034]. While, there was no relationship between genotypes of SNPs rs7970314 and rs4334089 and hospitalization. The TT genotype of rs11568820 plays protective role in sever COVID-19 and hospitalization. Further studies with a large sample size which consider various confounding factors are warranted to confirm our results.

Previous research has indicated an association between the presence of the vitamin D receptor (VDR) in breast cancer tissue and a favorable prognosis. This study aimed to further evaluate the prognostic potential of VDR located in the nuclear membrane or nucleus (liganded). The VDR protein levels were analyzed using immunohistochemistry in tumor samples from 878 breast cancer patients from Lund, Sweden, included in the Breast Cancer and Blood Study (BCBlood) from October 2002 to June 2012. The follow-up for breast cancer events and overall survival was recorded until 30 June 2019. Univariable and multivariable survival analyses were conducted, both with complete case data and with missing data imputed using multiple imputation by chained equations (MICE). Tumor-specific positive nuclear membrane VDR(num) staining was associated with favorable tumor characteristics and a longer breast cancer free interval (BCFI; HR: 0.64; 95% CI: 0.44-0.95) and overall survival (OS; HR: 0.52; 95% CI: 0.34-0.78). Further analyses indicated that VDRnum status also was predictive of overall survival when investigated in relation to ER status. There were significant interactions between VDR and invasive tumor size (Pinteraction = 0.047), as well as mode of detection (Pinteraction = 0.049). VDRnum was associated with a longer BCFI in patients with larger tumors (HR: 0.36; 95% CI: 0.14-0.93) or clinically detected tumors (HR: 0.28; 95% CI: 0.09-0.83), while no association was found for smaller tumors and screening-detected tumors. Further studies are suggested to confirm our results and to evaluate whether VDR should and could be used as a prognostic and targetable marker in breast cancer diagnostics.

Evidence regarding the relationships of serum 25-hydroxyvitamin D [25(OH)D] with cardiovascular diseases (CVD) and mortality among patients with chronic kidney disease (CKD) is limited and inconsistent.
This study aimed to investigate the associations between serum 25(OH)D and CVD incidence and mortality among patients with CKD.
This prospective study included 21,507 participants with CKD and free of CVD in the UK Biobank. Incidences of total and subtypes of CVD and mortality were ascertained via electronic health records. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) and 95% confidential intervals (CIs) for CVD incidence and mortality.
The median serum 25(OH)D concentration was 44.0 nmol/L (interquartile range: 30.1, 60.6 nmol/L). After multivariable adjustment, compared with CKD patients with serum 25(OH)D concentrations of <25 nmol/L, those with serum 25(OH)D ≥75 nmol/L had HRs (95% CIs) of 0.80 (0.71, 0.90) for total CVD incidence, 0.82 (0.69, 0.97) for ischemic heart disease, 0.56 (0.41, 0.77) for stroke, 0.64 (0.46, 0.88) for myocardial infarction, 0.62 (0.49, 0.80) for heart failure, 0.60 (0.43, 0.85) for CVD mortality, and 0.62 (0.52, 0.74) for all-cause mortality. In addition, these associations were not modified by vitamin D receptor polymorphisms, with no significant interaction detected.
Higher serum 25(OH)D concentrations were significantly associated with lower risks of total and subtypes of CVD incidence and mortality among individuals with CKD. These findings highlight the importance of maintaining adequate vitamin D status in the prevention of CVD and mortality in patients with CKD.

BACKGROUND: Vitamin D status has been associated with risk of type 2 diabetes (T2D), but evidence is scarce regarding whether such relation differs by glycemic status.
OBJECTIVE: To prospectively investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and risk of incident T2D across the glycemic spectrum and the modification effect of genetic variants in the vitamin D receptor (VDR).
METHODS: This prospective study included 379 699 participants without T2D at baseline from the UK Biobank. Analyses were performed according to glycemic status and HbA1c levels. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs.
RESULTS: During a median of 14.1 years of follow-up, 6315 participants with normoglycemia and 9085 patients with prediabetes developed T2D. Compared with individuals with 25(OH)D < 25 nmol/L, the multivariable-adjusted HRs (95% CIs) of incident T2D for those with 25(OH)D ≥ 75 nmol/L was 0.62 (0.56, 0.70) among the normoglycemia group and 0.64 (0.58, 0.70) among the prediabetes group. A significant interaction was observed between 25(OH)D and VDR polymorphisms among participants with prediabetes (P interaction = .017), whereby the reduced HR of T2D associated with higher 25(OH)D was more prominent in those carrying the T allele of rs1544410. Triglyceride levels mediated 26% and 34% of the association between serum 25(OH)D and incident T2D among participants with normoglycemia and prediabetes, respectively.
CONCLUSIONS: Higher serum 25(OH)D concentrations were associated with lower T2D risk across the glycemic spectrum below the threshold for diabetes, and the relations in prediabetes were modified by VDR polymorphisms. Improving the lipid profile, mainly triglycerides, accounted for part of the favorable associations.

BACKGROUND: Increasing evidence points at an important physiological role of the timekeeping system, known as the circadian clock (CC), regulating not only our sleep-awake rhythm but additionally many other cellular processes in peripheral tissues. It was shown in various cell types that environmental stressors, including ultraviolet B radiation (UV-B), modulate the expression of genes that regulate the CC (CCGs) and that these CCGs modulate susceptibility for UV-B-induced cellular damage. It was the aim of this pilot study to gain further insights into the CCs\' putative role for UV-B-induced photocarcinogenesis of skin cancer.
METHODS: Applying RT-PCR, we analyzed the expression of two core CCGs (brain and muscle ARNT-like 1 (Bmal1) and Period-2 (Per2)) over several time points (0-60 h) in HaCaT cells with and without 1,25-dihydroxyvitamin D (D3) and/or UV-B and conducted a cosinor analysis to evaluate the effects of those conditions on the circadian rhythm and an extended mixed-effects linear modeling to account for both fixed effects of experimental conditions and random inter-individual variability. Next, we investigated the expression of these two genes in keratinocytes representing different stages of skin photocarcinogenesis, comparing normal (Normal Human Epidermal Keratinocytes-NHEK; p53 wild type), precancerous (HaCaT keratinocytes; mutated p53 status), and malignant (Squamous Cell Carcinoma SCL-1; p53 null status) keratinocytes after 12 h under the same conditions.
RESULTS: We demonstrated that in HaCaT cells, Bmal1 showed a robust circadian rhythm, while the evidence for Per2 was limited. Overall expression of both genes, but especially for Bmal1, was increased following UV-B treatment, while Per2 showed a suppressed overall expression following D3. Both UVB and 1,25(OH)2D3 suggested a significant phase shift for Bmal1 (p < 0.05 for the acrophase), while no specific effect on the amplitude could be evidenced. Differential effects on the expression of BMAL1 and Per2 were found when we compared different treatment modalities (UV-B and/or D3) or cell types (NHEK, HaCaT, and SCL-1 cells).
CONCLUSIONS: Comparing epidermal keratinocytes representing different stages of skin photocarcinogenesis, we provide further evidence for an independently operating timekeeping system in human skin, which is regulated by UV-B and disturbed during skin photocarcinogenesis. Our finding that this pattern of circadian rhythm was differentially altered by treatment with UV-B, as compared with treatment with D3, does not support the hypothesis that the expression of these CCGs may be regulated via UV-B-induced synthesis of vitamin D but might be introducing a novel photoprotective property of vitamin D through the circadian clock.

The importance of Vitamin D in ovarian cancer (OC) has been well documented, and lower levels have been associated with susceptibility to OC. Vitamin D exerts its effect through the vitamin D receptor (VDR). Common genetic variants in the VDR gene (Fok I, TaqI, BamI and ApaI) have been linked with the susceptibility to the development of OC; however, the reports remain contradictory. To draw a valid conclusion, we performed a meta-analysis of the earlier published reports in the present study. The literature search was performed in PubMed, Google Scholar, and Scopus databases. All relevant articles were screened, and eligible reports were identified based on prefixed inclusion and exclusion criteria. Data such as author\'s details, year of publication, ethnicity, genotype and allele prevalence in cases and controls were extracted from the eligible reports. The meta-analysis was performed using Comprehensive Meta-analysis Software (CMA) V3. Eight articles, including data from fourteen independent cohorts, comprised 4276 cases and 6739 healthy controls considered for the analysis. VDR FokI and BamI variants revealed a significant association with an increased risk of OC. Other VDR polymorphisms (TaqI and ApaI) failed to demonstrate such an association with OC. Interestingly, the sensitivity analysis revealed minimal deviation from the parent meta-analysis, supporting the robustness of the present analysis. The trial sequential analysis revealed the inclusion of a sufficient number of studies for FokI polymorphism. It highlighted the requirement for additional case-control studies in VDR (ApaI, BamI and TaqI) to draw a definitive conclusion. FokI and BamI polymorphisms are associated with susceptibility to OC.