Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D.

Vitamin D status-a complex trait influenced by environmental and genetic factors-is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)-the main circulating form of vitamin D-in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D.

The immune cell transcriptome is modulated by vitamin D3 supplementation in people with a first demyelinating event participating in a randomized placebo-controlled trial.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

Vitamin D-binding protein deficiency: an underrecognized Mendelian disorder of vitamin D metabolism.

Vitamin D-binding protein (VDBP) deficiency is a recently discovered apparently benign biochemical disorder that can masquerade as treatment-resistant vitamin D deficiency and is likely underrecognized. We present the case of a child with persistently low 25OH vitamin D levels despite replacement therapy. Exome sequencing revealed a novel homozygous nonsense variant in the GC gene, leading to undetectable levels of VDBP. Interestingly, exome sequencing also revealed a homozygous loss-of-function variant in ZNF142, which likely explains the additional clinical features of recurrent febrile convulsions and global developmental delay. Our findings corroborate the two previously reported patients with autosomal recessive VDBP deficiency caused by biallelic GC variants and emphasize the importance of measuring VDBP levels in cases of apparent vitamin D deficiency that is treatment-resistant. We also urge caution in concluding "atypical" presentations without careful investigation of a potential dual molecular diagnosis.

Serum 25-Hydroxyvitamin D and Risk of Disability in Activities of Daily Living among the Oldest-Old: An Observational and Mendelian Randomization Study.

BACKGROUND: Vitamin D deficiency and disability are both prevalent among older adults. However, the association between them has rarely been investigated in the oldest-old subjects (aged ≥80 y), and the causality remains unclear. OBJECTIVE: This study aimed to elucidate the causal effect of vitamin D on the incident risk of disability in activities of daily living (ADL) among Chinese oldest-old based on the 2012-2018 Chinese Healthy Ageing and Biomarkers Cohort Study. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] concentrations and ADL status at baseline and follow-up interviews were documented. Cox regression models were applied among 1427 oldest-old (mean age, 91.2 y) with normal baseline ADL status. One sample Mendelian randomization (MR) analyses were performed on a subset of 941 participants with qualified genetic data, using a 25(OH)D-associated genetic risk score as the genetic instrument. RESULTS: During a median follow-up of 3.4 y, 231 participants developed disability in ADL. Serum 25(OH)D concentration was inversely associated with the risk of disability in ADL [per 10 nmol/L increase hazard ratio (HR) 0.85; 95% CI: 0.75, 0.96]. Consistent results from MR analyses showed that a 10 nmol/L increment in genetically predicted 25(OH)D concentration corresponded to a 20% reduced risk of ADL disability (HR 0.80; 95% CI: 0.68, 0.94). Nonlinear MR demonstrated a monotonic declining curve, with the HRs exhibiting a more pronounced reduction among individuals with 25(OH)D concentrations below 50 nmol/L. Subgroup analyses showed that the associations were more distinct among females and those with poorer health conditions. CONCLUSIONS: Our study supports an inverse causal relationship between serum 25(OH)D concentration and the risk of disability in ADL among Chinese oldest-old. This protective effect was more distinct, especially for participants with vitamin D deficiency. Appropriate measures for improving vitamin D might help reduce the incidence of physical disability in this specific age group.

Phenomewide Association Study of Health Outcomes Associated With the Genetic Correlates of 25 Hydroxyvitamin D Concentration and Vitamin D Binding Protein Concentration.

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS25OHD and PGSDBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.

Analysis of MicroRNA-Transcription Factors Co-Regulatory Network Linking Depression and Vitamin D Deficiency.

Depression and vitamin D deficiency are often co-occurring pathologies, the common pathogenetic ground of which includes an augmented inflammatory response. However, the molecular details of this relationship remain unclear. Here, we used a bioinformatic approach to analyze GEO transcriptome datasets of major depressive disorder (MDD) and vitamin D deficiency (VDD) to identify the hub genes within the regulatory networks of commonly differentially expressed genes (DEGs). The MDD-VDD shared regulatory network contains 100 DEGs (71 upregulated and 29 downregulated), with six hub genes (PECAM1, TLR2, PTGS2, LRRK2, HCK, and IL18) all significantly upregulated, of which PTGS2 (also known as COX2) shows the highest inference score and reference count. The subsequent analysis of the miRNA-transcription factors network identified COX2, miR-146a-5p, and miR-181c-5p as key co-regulatory actors in the MDD-VDD shared molecular pathogenic mechanisms. Subsequent analysis of published MDD and VDD transcriptome data confirmed the importance of the identified hub genes, further validating our bioinformatic analytical pipeline. Our study demonstrated that PTGS2 was highly upregulated in both depressive patients and patients with low vitamin D plasma levels. Therefore, regulators targeting PTGS2, like miR-146a-5p and miR181c-5p, may have great potential in controlling both diseases simultaneously, accentuating their role in future research.

Vitamin D deficiency and genetic polymorphisms of vitamin D-associated genes in Parkinson's disease.

Parkinson's disease (PD) and vitamin D share a unique link as vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of vitamin D biology in PD might be crucial for therapeutic strategies emphasising vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (vitamin D receptor) or GC (vitamin D binding protein) may aid the process along with polymorphisms of vitamin D metabolising genes (e.g., CYP2R1 and CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to vitamin D levels [GC (GC1-rs7041 and GC2-rs4588), CYP2R1, CYP24A1 and CYP27B1] and vitamin D function [VDR (FokI - rs2228570 and rs10735810; ApaI - rs7976091, rs7975232BsmI and rs1544410; and TaqI - rs731236)] was conducted to explore their relationship with PD severity globally. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, there by influencing PD pathophysiology. Knowledge of the polymorphisms associated with VDD appears promising for developing precision vitamin D-dosing therapeutic strategies against PD.

Serum sulfate level and Slc13a1 mRNA expression remain unaltered in a mouse model of moderate vitamin D deficiency.

Sulfate is essential for healthy foetal growth and neurodevelopment. The SLC13A1 sulfate transporter is primarily expressed in the kidney where it mediates sulfate reabsorption and maintains circulating sulfate levels. To meet foetal demands, maternal sulfate levels increase by twofold in pregnancy via upregulated SLC13A1 expression. Previous studies found hyposulfataemia and reduced renal Slc13a1 mRNA expression in rodent models with either severe vitamin D deficiency or perturbed vitamin D signalling. Here we investigated a mouse model of moderate vitamin D deficiency. However, serum sulfate level and renal Slc13a1 mRNA expression was not decreased by a moderate reduction in circulating vitamin D level. We confirmed that the mouse Slc13a1 5'-flanking region was upregulated by 1,25(OH)2D3 using luciferase assays in a cultured renal OK cell line. These results support the presence of a functional VDRE in the mouse Slc13a1 but suggests that moderate vitamin D deficiency does not impact on sulfate homeostasis. As sulfate biology is highly conserved between rodents and humans, we proposed that human SLC13A1 would be under similar transcriptional regulation by 1,25(OH)2D3. Using an online prediction tool we identified a putative VDRE in the SLC13A1 5'-flanking region but unlike the mouse Slc13a1 sequence, the human sequence did not confer a significant response to 1,25(OH)2D3 in vitro. Overall, this study suggests that moderate vitamin D deficiency may not alter sulfate homeostasis. This needs to be confirmed in humans, particularly during pregnancy when vitamin D and sulfate levels need to be maintained at high levels for healthy maternal and child outcomes.

Vitamin D deficiency and vitamin D receptor FokI polymorphism as risk factors for COVID-19.

BACKGROUND: Given the sparse data on vitamin D status in pediatric COVID-19, we investigated whether vitamin D deficiency could be a risk factor for susceptibility to COVID-19 in Egyptian children and adolescents. We also investigated whether vitamin D receptor (VDR) FokI polymorphism could be a genetic marker for COVID-19 susceptibility. METHODS: One hundred and eighty patients diagnosed to have COVID-19 and 200 matched control children and adolescents were recruited. Patients were laboratory confirmed as SARS-CoV-2 positive by real-time RT-PCR. All participants were genotyped for VDR Fok1 polymorphism by RT-PCR. Vitamin D status was defined as sufficient for serum 25(OH) D at least 30 ng/mL, insufficient at 21-29 ng/mL, deficient at <20 ng/mL. RESULTS: Ninety-four patients (52%) had low vitamin D levels with 74 (41%) being deficient and 20 (11%) had vitamin D insufficiency. Vitamin D deficiency was associated with 2.6-fold increased risk for COVID-19 (OR = 2.6; [95% CI 1.96-4.9]; P = 0.002. The FokI FF genotype was significantly more represented in patients compared to control group (OR = 4.05; [95% CI: 1.95-8.55]; P < 0.001). CONCLUSIONS: Vitamin D deficiency and VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents. IMPACT: Vitamin D deficiency could be a modifiable risk factor for COVID-19 in children and adolescents because of its immune-modulatory action. To our knowledge, ours is the first such study to investigate the VDR Fok I polymorphism in Caucasian children and adolescents with COVID-19. Vitamin D deficiency and the VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents. Clinical trials should be urgently conducted to test for causality and to evaluate the efficacy of vitamin D supplementation for prophylaxis and treatment of COVID-19 taking into account the VDR polymorphisms.

Association of rs2282679 polymorphism in vitamin D binding protein gene (GC) with the risk of vitamin D deficiency in an iranian population: season-specific vitamin D status.

BACKGROUND: Genome-wide association studies in Western countries indicate a considerable impact of variations in vitamin D binding protein (GC) genes on serum concentrations of 25-hydroxyvitamin D (25(OH)D). We aimed to investigate an association between rs2282679 polymorphism in GC and vitamin D deficiency. METHODS: A cross-sectional study conducted in the framework of the Tehran Cardio-Metabolic Genetic Study (TCGS) cohort. A total of 1568 participants aged > 18 years were randomly selected, and their 25(OH) D concentration was measured. Vitamin D deficiency was assessed concerning rs2282679 by descriptive and multivariate analysis, odds ratio (OR), and 95% confidence intervals (95%CI) calculated. Since the interaction term between rs2282679 and recruitment season was significant, we performed regression analysis separately for individuals whose blood was taken in high sunny and those whose blood was drawn in the low sunny season. RESULTS: The rs2282679 polymorphism was in Hardy-Weinberg equilibrium (P > 0.05) in the studied population. The serum concentration of 25(OH) D median was 15.0 ng/mL, and the prevalence of VDD was 27.8%. The presence of the G allele in rs2282679 increases the risk of VDD in additive (OR = 1.35, 95% CI: 1.06-1.73) and dominant (OR = 1.33, 95% CI: 1.06-1.68) genetic models. After separating participants based on the recruitment season, the unfavorable association was observed in the additive and dominant only in the low sunny season. CONCLUSION: The finding of the current study indicates that the GC rs2282679 SNP is associated with vitamin D deficiency. It seems that the impact of risk allele increased in the low sunny season when UV exposure has been declined.

The role of single nucleotide variant rs3819817 of the Histidine Ammonia-Lyase gene and 25-Hydroxyvitamin D on bone mineral density, adiposity markers, and skin pigmentation, in Mexican population.

PURPOSE: Vitamin D (VD) deficiency and osteoporosis have become a global public health problem. A variant in the Histidine Ammonia-Lyase (HAL) gene has been associated with VD levels and bone mineral density (BMD). However, whether this variant has an influence on VD levels and BMD in Mexican adults remain unclear. METHODS: This cross-sectional analysis included 1,905 adults participating in the Health Worker Cohort Study and 164 indigenous postmenopausal women from the Metabolic Analysis in an Indigenous Sample (MAIS) cohort. The rs3819817 variant was genotyped by TaqMan probe assay. Total 25 hydroxyvitamin D levels were measured by DiaSorin Liaison. BMD at the different sites was assessed through dual-energy X-ray absorptiometry. Linear and logistic regression models were performed to evaluate the associations of interest. RESULTS: The prevalence of VD deficiency was 41%, showing differences between sexes. Obesity and skin pigmentation were associated with lower levels of VD in males and females. rs3819817-T allele was associated with low levels of 25-hydroxyvitamin D, VD deficiency, and hip and femoral neck BMD values (g/cm2). We found two interactions with VD levels, one between adiposity and rs3819817-T allele (P = 0.017) and another between skin pigmentation and rs3819817-T allele (P = 0.019). In indigenous postmenopausal women, we observed higher VD levels in the southern region compared to the northern region (P < 0.001); however, we did not observe differences by genotype. CONCLUSION: Our findings confirm that the genetic variant rs3819817 has an essential function in VD levels and BMD and suggests a role in skin pigmentation in the Mexican population.

Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults.

Background & objectives: Despite being a tropical country, vitamin D deficiency is highly prevalent in India with studies indicating 40-99 per cent prevalence. Apart from calcium and phosphate metabolism, vitamin D is involved in cell cycle regulation, cardiovascular, hepatoprotection. The metabolism of vitamin D is regulated by vitamin D tool genes (CYP2R1/CYP27B1/CYP24A1/VDR). The promoter regions of some of these genes have CpG islands, making them prone to methylation induced gene silencing, which may cause a reduction in circulating vitamin D levels. Epigenetic basis of vitamin D deficiency is yet to be studied in India, and hence, this pilot study was aimed to analyze whether methylation levels of CYP2R1 gene were correlated with the levels of 25(OH)D in healthy, adult individuals in Indian population. Methods: In this cross-sectional study, healthy adults of 18-45 yr of age with no history of malabsorption, thyroidectomy, chronic illness or therapeutic vitamin D supplementation were recruited. DNA methylation analysis was carried out by methylation specific quantitative PCR. Serum calcium, phosphate and vitamin D levels were also quantified. Statistical analysis was done by R 4.0.5 software. Results: A total of 61 apparently healthy adults were analyzed. The serum vitamin D levels did not correlate with CYP2R1 methylation levels in our study population. Significant positive correlation was observed between age and serum vitamin D levels. Significant association of gender was found with CYP2R1 methylation levels. Interpretation & conclusions: This study found no significant correlation between levels of CYP2R1 methylation and circulating 25(OH)D deficiency. Further studies on the Indian population having a larger sample size including entire vitamin D tool genes, among different ethnic groups may be conducted to elucidate molecular etiology of circulating 25(OH)D deficiency. The high prevalence of normal serum calcium and phosphate levels among vitamin D deficient subjects in this study coupled with the strikingly high prevalence of the deficiency at the national level, may suggest the need to revise the cut-off criteria for vitamin D deficiency in the Indian population.

Association of vitamin D deficiency and vitamin D receptor (VDR) gene single-nucleotide polymorphism (rs7975232) with risk of preeclampsia.

BACKGROUND: Preeclampsia has a multifactorial-yet-elusive etiology. Recent reports suggest a link between preeclampsia and vitamin D (VD) metabolic axis. Genetic variations like single-nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) gene can alter the metabolic role of VD, which have been shown by several genetic association studies. However, there is discordance among these studies. OBJECTIVE: The current study aimed to investigate the association of VDR gene polymorphism (ApaI) and VD deficiency with risk of developing preeclampsia. PATIENTS AND METHOD: In this case-control study, 40 preeclamptic and 40 normotensive pregnant women were compared for VD status and VDR gene polymorphism. Serum 25-hydroxyvitamin-D [25(OH) D] level was determined by enzyme-linked immunosorbent assay (ELISA) and VDR gene polymorphism Apa1 was analyzed by Allele specific polymerase chain reaction (AS-PCR) using sequence specific primers. RESULTS: Serum levels of 25(OH) D were very low but comparable in both preeclamptic and normotensive pregnant women. The difference between the two groups were not statistically significant (p = .423). VDR gene polymorphism ApaI (rs7975232) was found not to have significant association with the risk of developing preeclampsia. The frequencies of wild genotype (GG) in preeclamptic and normotensive women were 27.5% and 22.5% respectively. A total of 25% of preeclamptic women had mutant homozygous genotype (TT) and 17.5% of normotensive women had mutant homozygous genotype. The frequency of mutant heterozygous genotype (GT) in preeclamptic patients was 47.5% and in normotensive women was 60%. The variation of wild and mutant genotypes between the two groups was not statistically significant (p > .05). CONCLUSION: This study showed that VDR gene polymorphism (ApaI) and VD deficiency are not associated with the risk of preeclampsia.

Vitamin D metabolic pathway genes polymorphisms and vitamin D levels in association with neonatal hyperbilirubinemia in China: a single-center retrospective cohort study.

BACKGROUND: Neonatal hyperbilirubinemia (NH) is a major cause of hospitalization after birth. Previous studies indicated that vitamin D deficiency might play an important role in NH susceptibility, but the results were controversial. Meanwhile, there has been limited description of the association between vitamin D related genes single nucleotide polymorphisms (SNP) and NH susceptibility. We aimed to investigate the vitamin D metabolic pathway genes polymorphisms and vitamin D levels with NH susceptibility. METHODS: We retrospectively analyzed the clinical data, vitamin D levels and its metabolic pathway gene polymorphisms of 187 NH neonates and 149 controls at Tianjin Children's Hospital/Tianjin University Children's Hospital between April 2019 and August 2022. Vitamin D levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and the genetic polymorphism of NADSYN1/DHCR7, GC, CYP2R1, CYP24A1 and CYP27B1 was detected by high resolution melting (HRM) analysis. RESULTS: The frequency of vitamin D deficiency (25(OH)D < 15 ng/mL) was significantly increased in the NH group compared to controls. TT genotype of rs12785878 and GT genotype of rs10877012 were protective factors of vitamin D deficiency and NH, and GT genotype and dominant model carriers of rs12785878 had a higher risk of severe NH than the GG genotype carriers (GT genotype: OR: 2.43; 95% CI: 1.22-4.86; P = 0.012, dominant model: OR: 1.97; 95% CI: 1.04-3.73; P = 0.037). GC gene haplotype was associated with vitamin D deficiency. No significant SNP-SNP and SNP-vitamin D levels interaction combinations were found. CONCLUSIONS: There were associations among NH, vitamin D deficiency and NADSYN1/DHCR7 and CYP27B1 polymorphisms, TT genotype of rs12785878 and GT genotype of rs10877012 could reduce the risk of vitamin D deficiency and NH. Furthermore, rs12785878 was significantly associated with severe NH.

Increased susceptibility to complicated pneumonia among egyptian children with FokI (rs2228570), not TaqI (rs731236), vitamin D receptor gene polymorphism in association with vitamin D deficiency: a case-control study.

BACKGROUND: Determining a genetic contribution to the development of complicated community-acquired pneumonia in children may help understand underlying pathogenesis. We aimed to investigate the association between two vitamin D receptor (VDR) gene polymorphisms, FokI and TaqI, and susceptibility to complicated pneumonia in Egyptian children compared to uncomplicated pneumonia. Associations with 25 hydroxy-vitamin D serum level were studied. METHODS: This was a case-control study that included 320 participants divided into 2 groups: patients and controls. The patients' group included 100 children hospitalized with complicated pneumonia and 100 with uncomplicated pneumonia. 120 age and sex-matched apparently healthy children served as controls. The VDR FokI and TaqI polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. 25 hydroxy-vitamin D level was estimated in serum using ELISA. RESULTS: Regarding FokI, homozygous CC genotype was more common in complicated (52%) than uncomplicated pneumonia (28%) and controls (10%) (OR = 65; 95%CI (5.13-822.63), p < 0.001) and (OR = 4.3; 95%CI (0.7-27.16), p = 0.003), respectively. Children carrying C allele possessed 3 higher odds for complicated than uncomplicated pneumonia (OR = 3.08; 95%CI (1.33-7.14), p < 0.001). Heterozygous CT genotype increased susceptibility to complicated pneumonia (OR = 13.7; 95%CI (4.6-40.1), p < 0.001), not uncomplicated pneumonia (OR = 1.56; 95%CI (0.86-2.85), p = 0.145). Among complicated pneumonia, vitamin D level was lower in CC (6.92 ± 2.6ng/ml) than CT (9.55 ± 3.2 ng/ml) and TT genotype carriers (13.13 ± 3.6ng/ml) (p < 0.001). There was no significant difference between patients and controls as regards TaqI genotypes and alleles. CONCLUSION: In association with vitamin D deficiency, VDR gene FokI polymorphism, not TaqI, is a genetic risk factor for complicated pneumonia in Egyptian children.

Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study.

BACKGROUND: Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking. OBJECTIVE: To assess genetic evidence for the causal role of low vitamin D status in mortality. DESIGN: Nonlinear Mendelian randomization analyses. SETTING: UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010. PARTICIPANTS: 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data. MEASUREMENTS: Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020. RESULTS: There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L. LIMITATIONS: Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate. CONCLUSION: Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels. PRIMARY FUNDING SOURCE: National Health and Medical Research Council.

Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases.

It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk.

AIMS: Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk. METHODS AND RESULTS: The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%). CONCLUSION: Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status.

Genotype Prevalence of Lactose Deficiency, Vitamin D Deficiency, and the Vitamin D Receptor in a Chilean Inflammatory Bowel Disease Cohort: Insights from an Observational Study.

Lactose intolerance (LI) and vitamin D deficiency (VDD) have been linked to inflammatory bowel disease (IBD). We conducted an observational study in 192 Chilean IBD patients to investigate the prevalence of a specific gene variant (LCT-13910 CC genotype) associated with LI and the prevalence of VDD/Vitamin D Receptor (VDR) gene variants. Blood samples were analyzed using Illumina's Infinium Global Screening Array. The LCT-13910 CC genotype was found in 61% of IBD patients, similar to Chilean Hispanic controls and lower than Chilean Amerindian controls. The frequency of the LCT-13910-C allele in Chilean IBD patients (0.79) was comparable to the general population and higher than Europeans (0.49). Regarding VDR and VDD variants, in our study, the rs12785878-GG variant was associated with an increased risk of IBD (OR = 2.64, CI = 1.61-4.32; p-value = 0.001). Sixty-one percent of the Chilean IBD cohort have a genetic predisposition to lactose malabsorption, and a significant proportion exhibit genetic variants associated with VDD/VDR. Screening for LI and VDD is crucial in this Latin American IBD population.