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Genetic and epigenetic factors influencing vitamin D status
Abstract
The global prevalence of vitamin D deficiency appears to be increasing, and the impact of this on human health is important because of the association of vitamin D insufficiency with increased risk of osteoporosis, cardiovascular disease and some cancers. There are few studies on the genetic factors that can influence vitamin D levels. In particular, the data from twin and family-based studies have reported that circulating vitamin D concentrations are partially determined by genetic factors. Moreover, it has been shown that genetic variants (e.g., mutation) and alteration (e.g., deletion, amplification, inversion) in genes involved in the metabolism, catabolism, transport, or binding of vitamin D to it receptor, might affect vitamin D level. However, the underlying genetic determinants of plasma 25-hydroxyvitamin D3 [25(OH)D] concentrations remain to be elucidated. Furthermore, the association between epigenetic modifications such as DNA methylation and vitamin D level has now been reported in several studies. The aim of current review was to provide an overview of the possible value of loci associated to vitamin D metabolism, catabolism, and transport as well epigenetic modification and environmental factors influencing vitamin D status. This article is protected by copyright. All rights reserved
... Despite abundant sunshine, the high prevalence of vitamin D deficiency is a mystery in a subtropical country like Bangladesh. Genetic factors affecting dermal synthesis and sun avoiding behavior may be an explanation [4]. Also, all these reported level of vitamin D at which deficiency has been defined is according to the cut off values recommended by the different international bodies. ...
... On the contrary, the garment workers who had minimum sun-exposure had the lowest prevalence (23%) of vitamin D deficiency compared to maximum sun exposed (≥8h/d) occupations -DFIW (77%) and fishermen (71%) (Table3a). Furthermore, the least sun-exposed (garments workers) had the highest vitamin D level, which differed significantly from other groups (Table -4a).Vitamin D level depends on genetic, epigenetic and environmental factors [4]. As the population belonged to low socioeconomic class, poor nutrition may have contributed to the low levels. ...
... In addition to environmental factors, there is an influence of genetic polymorphism on serum 25(OH)D and 1,25(OH) vitamin D levels. Several steps of vitamin D metabolism are under genetic control [4]. Although the genetic influence of vitamin D is still poorly understood, family studies in different populations have found that genetic factors contribute to 70% of the variation in serum vitamin D level [20]. ...
Background and objectives: Recent publications have reported alarming prevalence of hypovitaminosis D in South Asian countries including Bangladesh. But, data on vitamin D levels in different occupational groups are lacking. This study addressed the prevalence of hypovitaminosis D in different occupational groups of Bangladesh. Additionally, the study estimated parathyroid hormone, phosphate, calcium and metabolic syndrome in these groups to see the effect of hypovitaminosis D on these parameters. Materials and method: Seven diverse occupational groups (agrarian workers, rickshaw-pullers, young cricketers and footballers, fishermen, dry fish industry workers, garment-workers and medical students) of Bangladesh were selected based on grade of physical activity and level of sun exposure. Blood was collected for the estimation of 25(OH) vitamin D, fasting glucose,lipid profiles, calcium, phosphate, magnesium and intact parathyroid (iPTH) hormone. Multiple comparisons of these variables among the 7 groups were estimated by ANOVA. Results: A total of 785 (m / f = 359 / 426) participants volunteered. Of them, 54.2% had vitamin D deficiency. Metabolic syndrome was 5% and showed no significant association with hypovitaminosis D (x2 = 0.9, p=0.43). For biophysical characteristics, the mean (±SD) values of age, body mass index, waist to hip ratio and waist to height ratio were – 33.8±16.3y, 22.3±4.1 kg/m2, 0.87±0.06 and 0.39±0.16, respectively. The values for vitamin D (ng/ml), calcium (mg/dl), iPTH (pgm/ml) and phosphate (mg/dl) were 20.25±13.1, 9.57±1.85, 38.22±24.54 and 4.18±0.81, respectively. The comparisons of vitamin D and other related variables among the groups (ANOVA) showed vitamin D level in the garments worker was significantly (p<0.01) higher from other 6 groups. Likewise, compared with other six, rickshaw-pullers had significantly higher calcium level. Calcium, phosphate and parathyroid hormone did not show any change with decreasing vitamin D level (high to low quartile: Q4→Q1), though parathyroid hormone increased significantly at the lowest vitamin D level (Q1:<11.8ng/ml: p=0.002). Conclusion: The prevalence of hypovitaminosis D was high irrespective of occupations, site (rural/urban), social class and sun-exposure. Overall, vitamin D level was low though varied among the groups. Despite minimum and maximum sun-exposure, the garments workers had the highest and the fishermen had the lowest vitamin D levels, respectively. Calcium level was normal in all groups. Calcium, phosphate and parathyroid hormone did not show any changes with decreasing vitamin D, though parathyroid hormone increased significantly when vitamin D decreased to the lowest quartile. The findings indicate that the specific cut off value for vitamin D deficiency needs to be determined for population of a given geographic area. IMC J Med Sci. 2023; 17(2):001. DOI: https://doi.org/10.55010/imcjms.17.011 *Correspondence: M Abu Sayeed, Department of Community Medicine, Ibrahim Medical College, 1/A, Ibrahim Sarani, Segunbagicha, Dhaka 1000, Bangladesh. Email: sayeed1950@gmail.com
... [173,174] Moreover, it has been shown that genetic variants (e.g., mutation) and alterations (e.g., deletion, amplification, and inversion) in genes involved in the metabolism, catabolism, transport, or even binding of vitamin D to its receptor might have an effect on vitamin D levels. [175] However, the underlying genetic determinants of 25(OH)D plasma levels have not been fully elucidated. Furthermore, the association between epigenetic modifications such as DNA methylation and vitamin D levels have now been reported in several studies. ...
... Furthermore, the association between epigenetic modifications such as DNA methylation and vitamin D levels have now been reported in several studies. [175] Linkage studies, studies involving candidate genes in the vitamin D metabolism pathway, as well as genome wide association studies (GWAS) have shown human genetic variants to be related to vitamin D status. ...
... Single nucleotide polymorphisms: Candidate gene studies and GWAS have shown that certain gene single nucleotide polymorphisms (SNP) involved in vitamin D metabolism pathways (e.g., CYP2R1, CYP27B1, CYP24A1, DHCR7, the VDR, and GC) have an effect on vitamin D levels as shown in Ref [175]. Vitamin D binding protein (VDBP) is discussed in detail further down in this article, but, briefly, VDBP has two common SNPs (rs7041 and rs4588), which results in three VDBP isotypes (Gc1f, Gc1s, and Gc2). ...
Vitamin D, an important hormone with a central role in calcium and phosphate homeostasis, is required for bone and muscle development as well as preservation of musculoskeletal function.The most abundant vitamin D metabolite is 25-hydroxyvitamin D [25(OH)D], which is currently considered the best marker to evaluate overall vitamin D status. 25(OH)D is therefore the most commonly measured metabolite in clinical practice. However, several other metabolites, although not broadly measured, are useful in certain clinical situations. Vitamin D and all its metabolites are circulating in blood bound to vitamin D binding protein, (VDBP). This highly polymorphic protein is not only the major transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites, but also participates in the transport of the 25(OH)D into the cell via a megalin/cubilin complex.
The accurate measurement of 25(OH)D has proved a difficult task. Although a reference method and standardization program are available for 25(OH)D, the other vitamin D metabolites still lack this. Interpretation of results, creation of clinical supplementation, and generation of therapeutic guidelines require not only accurate measurements of vitamin D metabolites, but also the accurate measurements of several other “molecules” related with bone metabolism.
IFCC understood this priority and a committee has been established with the task to support and continue the standardization processes of vitamin D metabolites along with other bone-related biomarkers.
In this review, we present the position of this IFCC Committee on Bone Metabolism on the latest developments concerning the measurement and standardization of vitamin D metabolites and its binding protein, as well as clinical indications for their measurement and interpretation of the results.
... Genetic variants of proteins participating in the vitamin D metabolism, its binding to receptors and transport can have an impact on vitamin D availability and status (5,7). Several single nucleotide polymorphisms (SNPs) related with serum 25(OH)D that have been detected in candidate gene studies and genome-wide association studies (GWAS) have enhanced our understanding of vitamin D balance; the detection of individuals more vulnerable to deficiency; as well as those who could benefit more than others from supplementation (5). ...
... Genetic variants of proteins participating in the vitamin D metabolism, its binding to receptors and transport can have an impact on vitamin D availability and status (5,7). Several single nucleotide polymorphisms (SNPs) related with serum 25(OH)D that have been detected in candidate gene studies and genome-wide association studies (GWAS) have enhanced our understanding of vitamin D balance; the detection of individuals more vulnerable to deficiency; as well as those who could benefit more than others from supplementation (5). The Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (the SUNLIGHT study) is the largest GWAS published to date that identified significant genetic determinants of 25(OH)D levels. ...
... The DBP has the highest affinity for 25(OH)D-lactones, followed by 25(OH)D and 1,25(OH) 2 D (72) and binds more effectively to vitamin D3 and its metabolites than vitamin D2 and its metabolites (73). Variants of the DBP gene have been widely investigated as sources of variation in the circulating levels of vitamin D (5,32). ...
Recent advances in the field of nutrigenetics have provided evidence on how genetic variations can impact the individuals' response to dietary intakes. An objective and reliable assessment of dietary exposures should rely on combinations of methodologies including frequency questionnaires, short-term recalls or records, together with biological samples to evaluate markers of intake or status and to identify genetic susceptibilities. In an attempt to present current knowledge on how genetic fingerprints contribute to an individual's nutritional status, we present a review of current literature describing associations between genetic variants and levels of well-established biomarkers of vitamin status in free-living and generally healthy individuals. Based on the outcomes of candidate gene, genome-wide-association studies and meta-analyses thereof, we have identified several single nucleotide polymorphisms (SNPs) involved in the vitamins' metabolic pathways. Polymorphisms in genes encoding proteins involved in vitamin metabolism and transport are reported to have an impact on vitamin D status; while genetic variants of vitamin D receptor were most frequently associated with health outcomes. Genetic variations that can influence vitamin E status include SNPs involved in its uptake and transport, such as in SCAR-B1 gene, and in lipoprotein metabolism. Variants of the genes encoding the sodium-dependent vitamin C transport proteins are greatly associated with the body's status on vitamin C. Regarding the vitamins of the B-complex, special reference is made to the widely studied variant in the MTHFR gene. Methodological attributes of genetic studies that may limit the comparability and interpretability of the findings are also discussed. Our understanding of how genes affect our responses to nutritional triggers will enhance our capacity to evaluate dietary exposure and design personalized nutrition programs to sustain health and prevent disease.
... Genetic polymorphisms have been found to affect vitamin D levels; such variants are found in genes encoding dehydrocholesterol reductase-7 (DHCR7) [134], nicotinamide adenine dinucleotide synthetase-1 (NADSYN1) [134], the gene encoding the group-specific component (GC) for DBP [135,136], and in several genes encoding cytochrome P450 (CYP) enzymes involved in the formation of 25(OH)D and 1,25(OH)2D and in the inactivation of 1,25(OH)2D (CYP2R1, CYP27B1, and CYP24A1) [134,136]. ...
... Genetic polymorphisms have been found to affect vitamin D levels; such variants are found in genes encoding dehydrocholesterol reductase-7 (DHCR7) [134], nicotinamide adenine dinucleotide synthetase-1 (NADSYN1) [134], the gene encoding the group-specific component (GC) for DBP [135,136], and in several genes encoding cytochrome P450 (CYP) enzymes involved in the formation of 25(OH)D and 1,25(OH)2D and in the inactivation of 1,25(OH)2D (CYP2R1, CYP27B1, and CYP24A1) [134,136]. ...
There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D–VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D–VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.
... Vitamin D deficiency status has been demonstrated to be influenced by several genetic factors, including genes involved with its synthesis and metabolism [13,14]. The 7dehydrocholesterol reductase gene (DHCR7) encodes the enzyme that converts 7-dehydrocholes terol (7DHC) to cholesterol, [15][16][17], and the 25-hydroxylase gene (CYP2R1) encodes the enzyme that converts vitamin D to the circulating form 25(OH)D [16][17][18]. ...
... Finally, the calcium sensing receptor gene (CASR), which is important in regulating calcium homeostasis and synthesis of the parathyroid hormone (PTH), has been shown to stimulate the synthesis of 1,25-dihydroxyvitamin D [23,24]. Numerous studies have identified genetic variants associated with vitamin D status and those genetic markers have been validated as genetic instruments for low vitamin D concentrations [13,16,21]. ...
The Ghanaian population is experiencing an upsurge in obesity and type 2 diabetes (T2D) due to rapid urbanization. Besides dietary factors, vitamin D-related genetic determinants have also been shown to contribute to the development of obesity and T2D. Hence, we aimed to examine the interactions between dietary factors and vitamin D-related genetic variants on obesity and T2D related outcomes in a Ghanaian population. Three hundred and two healthy Ghanaian adults (25–60 years old) from Oforikrom, Municipality in Kumasi, Ghana were randomly recruited and had genetic tests, dietary consumption analysis, and anthropometric and biochemical measurements of glucose, HbA1c, insulin, cholesterol, and triglycerides taken. A significant interaction was identified between vitamin D-GRS and fiber intake (g/day) on BMI (pinteraction = 0.020) where those who were consuming low fiber (≤16.19 g/d) and carrying more than two risk alleles for vitamin D deficiency (p = 0.01) had a significantly higher BMI. In addition, an interaction between vitamin D-GRS and fat intake (g/day) on HbA1c (total fat, pinteraction = 0.029) was found, where participants who had a lower total fat intake (≤36.5 g/d), despite carrying more than two risk alleles, had significantly lower HbA1c (p = 0.049). In summary, our study has identified novel gene–diet interactions of vitamin D-GRS with dietary fiber and fat intakes on metabolic traits in Ghanaian adults.
... However, the maximum LOD score was (1.16) for a locus on chromosome 14, which was insignificant according to Tang and Siegmund's mapping technique [42]. Bahrami et al. [43] reported that various methods of detecting vitD levels and polygenic variation in serum vitD might make linkage studies unsuccessful. Despite linkage studies may fail to identify replicated genetic architecture of vitD metabolism, GWAS and the candidate gene approach have shown reproducible influences of gene control on vitD status. ...
... The CYP27B1 gene (cytochrome P450 family 27 subfamily B member 1; mapped on human chromosome 12, q13.1-q13.3, 6.66 kb fragment) encodes 1α-hydroxylase which is involved in the second process to yield calcitriol [43] (Fig. 2B). The CYP27B1-1260 Major C allele genotypes of rs2248359 were more frequent in AD patients compared with the healthy volunteers (OR=2.10; ...
Background
Vitamin D is a fat-soluble vitamin, and it is a potential key factor to maintain a healthy status. Various observational studies have reported the association between vitamin D deficiency and an elevated risk of osteoporosis, cardiovascular disease, diabetes mellitus, and certain types of cancers. The number of studies that investigated the genetic determinants of vitamin D hydroxy metabolism has been growing, still, its association with the genetic variants remains unclear, particularly those genes related to vitamin D metabolism.
Aim
This work is a comprehensive review of available evidence of the effect of genetic variants on vitamin D metabolism and their impact on vitamin D status in the human body, disorders including coronavirus disease 2019 infection, and its importance for clinical investigators and public health.
Results
Genome-wide association studies and candidate gene studies show that circulating levels of vitamin D are being influenced by genetic factors. These genetic changes are implicated in various pathways of vitamin D, such as metabolism and transport. It is also involved in the formation of the ternary complex (vitamin D receptor - retinoid receptor - transcription factor II B).
Conclusion
Linkage studies may fail to identify replicated genetic architecture of vitD metabolism, Genome-wide association studies and the candidate gene approach have shown reproducible influences of gene control on vitD status.
... Previous studies on VD have found that genetic and environmental factors can affect the status and metabolism of VD. The data from twin and family studies have suggested that circulating VD concentrations are partly determined by genetics, with heritability ranging from 23% to 80% [7]. Furthermore, genetic studies of VD have found that genetic variations and alterations (e.g., deletions, amplifications, inversions) in genes involved in VD metabolism, catabolism, transport, or binding to its receptors may affect VD levels [7]. ...
... The data from twin and family studies have suggested that circulating VD concentrations are partly determined by genetics, with heritability ranging from 23% to 80% [7]. Furthermore, genetic studies of VD have found that genetic variations and alterations (e.g., deletions, amplifications, inversions) in genes involved in VD metabolism, catabolism, transport, or binding to its receptors may affect VD levels [7]. Moreover, a study of gene-environment interactions with VD has showed that specific genetic variants associated with VD metabolism may be correlated with prostate cancer risk in VD-deficient patients [8]. ...
Previous studies have suggested that vitamin D (VD) was associated with psychiatric diseases, but efforts to elucidate the functional relevance of VD with depression and anxiety from genetic perspective have been limited. Based on the UK Biobank cohort, we first calculated polygenic risk score (PRS) for VD from genome-wide association study (GWAS) data of VD. Linear and logistic regression analysis were conducted to evaluate the associations of VD traits with depression and anxiety traits, respectively. Then, using individual genotype and phenotype data from the UK Biobank, genome-wide environment interaction studies (GWEIS) were performed to identify the potential effects of gene × VD interactions on the risks of depression and anxiety traits. In the UK Biobank cohort, we observed significant associations of blood VD level with depression and anxiety traits, as well as significant associations of VD PRS and depression and anxiety traits. GWEIS identified multiple candidate loci, such as rs114086183 (p = 4.11 × 10−8, LRRTM4) for self-reported depression status and rs149760119 (p = 3.88 × 10−8, GNB5) for self-reported anxiety status. Our study results suggested that VD was negatively associated with depression and anxiety. GWEIS identified multiple candidate genes interacting with VD, providing novel clues for understanding the biological mechanism potential associations between VD and psychiatric disorders.
... L. reuteri NCIMB 30242 with bile salt hydrolase functionality decreased the LDL-c and increased the circulating bile acid. L. reuteri NCIMB 30242 also increases the serum 25-hydroxyvitamin D (25.5%), which significantly reduces the risk of osteoporosis, CVD, diabetes, and some cancers [44,45]. It may reduce CVD risk and other chronic diseases [46]. ...
... Authors have also analyzed the increased circulation of 25-hydroxyvitamin D in serum during L. reuteri NCIMB administration and found that the level of vitamin D was increased at the end of the study. The increased vitamin D level improves the proper intestinal colonization of probiotics, prevents pathogenic bacterial invasion, reduces chronic inflammation, and maintains enterocyte cell integrity [45,64,65]. Women who consumed yogurt containing L. acidophilus 145 and B. longum 913 regularly for six months had higher HDL-c levels and improved LDL-c/HDL-c ratio [52]. ...
Hypercholesterolemia is a key factor in the progression of atherosclerosis and cardiovascular disease (CVD). CVD is a significant public health concern with a high death rate. Some of the main factors linked to CVD include genetics and lifestyle. Dyslipidemia has been one of the factors related to the onset of several CVD-related diseases. Several clinicopathological studies have shown a correlation between high cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-c), and CVD development. Probiotics have received a lot of attention for various beneficial effects, especially their ability to reduce blood cholesterol in humans. Probiotics were shown in several investigations to affect hypercholesterolemia by influencing cholesterol biosynthesis. The current review focuses on the human dietary interventions with probiotics and their effects on CVD risk factors and hypercholesterolemia. The outcomes are debatable and consider various parameters such as probiotic strain, dosing frequency, therapeutic response, dietary changes, and so forth. As a result, probiotics have the propensity to become dietary supplements in moderate/severe hypercholesterolemic patients, which significantly reduces the CVD risk.
... In recent years there is new evidence that vitamin-D levels are not only dependent on sun exposure and diet [1], but are also to a significant degree determined genetically [6,7]. This, and vitamin D's possible association with numerous diseases, amplifies the value of being able to predict vitamin-D levels in an individual over time. ...
... The serum 25(OH)D level is partly genetically determined, and several single nucleotide polymorphisms in enzymes necessary for production, transport, and degradation of the active vitamin-D metabolite 1,25-dihydroxyvitamin D have been described [6,30]. These genetic differences may account for a large part of the variation in serum 25(OH)D levels [7]. However, the main determinants of serum 25(OH)D levels are amendable factors related to lifestyle, like time spent in the sun, intake of vitamin-D-rich food like fatty fish, and the use of vitamin-D supplement [1,30]. ...
Background/objectives
Our objective was to evaluate the degree of tracking for serum levels of 25-hydroxyvitamin D [25(OH)D] over time, by using data from three previously conducted surveys of the Tromsø study collected in the years 1994/1995 (Tromsø 4), 2007/2008 (Tromsø 6), and 2015/2016 (Tromsø 7).
Subjects/methods
Subjects with valid 25(OH)D measurements in all three surveys were included. 25(OH)D z-scores were used to adjust for seasonal variation. Z-scores and sextiles were used to illustrate tracking of 25(OH)D.
Results
1702 subjects (572 males, 1130 females) fulfilled the inclusion criteria. Median (5th, 95th percentiles) age for these subjects was 55 (33, 65) years in Tromsø 4, and mean (SD) 25(OH)D levels were 57 (18) nmol/L, 59 (19) nmol/L, and 72 (21) nmol/L for Tromsø 4, Tromsø 6, and Tromsø 7, respectively. There was significant tracking of serum 25(OH)D over the 21 years period between the surveys of the Tromsø study. The correlation coefficient r between 25(OH)D z-scores from Tromsø 4 and Tromsø 6 was 0.40, and declined to 0.29 for the correlation between Tromsø 4 and Tromsø 7. Twenty-six percent of the subjects in the lowest 25(OH)D z-score sextile in Tromsø 4 were in the three highest sextiles of 25(OH)D in Tromsø 7. Similarly, 35% of those in the highest sextile in Tromsø 4 were in the lowest three sextiles in Tromsø 7.
Conclusions
The degree of tracking for serum 25(OH)D declines over time, and the use of a single serum 25(OH)D measurement as an indicator of the vitamin-D status is questionable if used in long-lasting observational studies.
... Because vitamin D3 acts through VDR, changes in this molecule e.g., as a result of polymorphisms occurring in the VDR gene, may have a key influence on the vitamin D concentration in the circulation, and the final biological activity. The most common single nucleotide polymorphisms (SNP) in the gene VDR are Apa-1 (rs7975232), Bsm-1 (rs1544410), Fok-1 (rs2228570), and Taq-1 (rs731236) [12,13]. ...
... For example, a genome-wide DNA methylation study by Adaikalakoteswari et al. associated vitamin B12 deficiency with reduced methylation of the sterol regulatory element (SREBF1) and LDL receptor (LDLR) genes, thus, increasing their expression as well as cholesterol biosynthesis [39]. Similarly, a reciprocal relationship has been shown between vitamin D levels and DNA methylation of genes of the Cytochrome P450 family involved in its metabolism [40]. These mechanisms warrant further investigation as interindividual variability could help to explain why neither vitamin D nor B12 supplementation have shown to be beneficial for CVD prevention in individuals without deficiencies [41][42][43]. ...
Background: Cardiovascular diseases (CVD) are the leading cause of death globally, making their prevention a major challenge for modern society. For decades, treatments aimed at reducing CVD risk factors through nutritional recommendations and medications have had variable success. One of the main reasons behind this is the interindividual variability in response to drugs and nutritional interventions. The development of genomics has allowed the discovery of genetic variants influencing drug and food response, leading to more personalized treatments in the form of precision medicine and precision nutrition. The latter is based on the principle that one diet does not fit all and the need to stratify individuals into subgroups based on their response to nutrients. Despite showing great promise in pushing forward the field of nutrition, health professionals have very little knowledge of precision nutrition, even though the general population is showing interest in more personalized nutritional guidance.
Summary: This review aims to provide an overview of key sources of interindividual variability observed in CVD risk factors in response to nutritional interventions. Despite some limitations, genetic testing is a mature predictive tool that should be at the forefront of tailored nutrition recommendations for CVD prevention. Although the epigenome-diet relationship shows great promise, it is still too early in its development to allow for its clinical deployment. Metabolomics has the potential to enhance genetic testing by complementing traditional self-reported dietary intake instruments as well as a very promising metabotyping method. Microbiome phenotyping, despite its complexity, provides a wealth of information on the health status of the host and its response to nutrients. Finally, current applications are discussed and an outline of the required steps for a successful implementation of precision nutrition in clinical practice as a tool for CVD prevention is presented.
Key Messages: Precision nutrition is the cornerstone of a promising approach offering targeted nutritional recommendations for CVD prevention.
... In addition, VDR BsmI polymorphism plays a key role in bone metabolism regulation [50]. The VDR gene codifies instructions for making VDR protein respond to 25(OH)D [115]. After combining with 25(OH)D, VDR regulates the proliferation and differentiation of osteoblasts, osteoclasts, and chondrocytes [90]. ...
Background
Children with idiopathic scoliosis (IS) have a high risk of osteoporosis and IS with low bone mineral density (BMD) are susceptible to curve progression. This review aims to explore the risk factors of low BMD in children with IS.
Methods
Studies were retrieved from 5 databases that were published up to January 2022. Search terms are keywords in titles or abstracts, including subject headings related to “Scoliosis”, “Bone Mineral Density”, and “Risk Factors”. Observational studies on risk factors of low BMD in children with IS were enrolled in this review. The number of studies, sample size, outcome measures, research type, endocrine, and lifestyle-related factors, gene/signal pathway, and other contents were extracted for qualitative analysis.
Results
A total of 56 studies were included in this scoping review. Thirty studies involved genetic factors that may affect BMD, including the Vitamin-D receptor gene, RANK/RANKL signal pathway, the function of mesenchymal stem cells, Runx2, Interleukin-6 (IL-6), and miR-145/β-catenin pathway. Eight studies mentioned the influence of endocrine factors on BMD, and the results showed that serum levels of IL-6, leptin and its metabolites, and ghrelin in children with IS were different from the age-matched controls. In addition, there were 18 articles on lifestyle-related factors related to low BMD in children with IS, consisting of physical activity, calcium intake, Vitamin D level, and body composition.
Conclusions
Genetic, endocrine, and lifestyle-related factors might relate to low BMD and even osteoporosis in IS. To prevent osteoporosis, the effectiveness of regular screening for low BMD risk factors in children with IS needs to be investigated. Additionally, clear risk factors suggest strategies for bone intervention. Future studies should consider the effectiveness of calcium and vitamin D supplements and physical activity in BMD improvement.
... Histone deacetylation and acetylation are controlled by histone deacetylases and histone acetyltransferases, respectively. Histone modifications of vitamin D receptors have been implicated in the pathophysiology of ASD (Bahrami et al. 2018). ...
Nutrition is vital for normal brain functions. Psychiatric disorders constitute a major percentage of disability worldwide and impose economic, social, and health burdens. Current treatments are focused on pharmacotherapy and psychotherapy. Nevertheless, such therapies prevent only about 50% of the disease’s impact, revealing that new approaches are required to prohibit and cure psychiatric diseases. Appropriate dietary nutrition helps in the prevention and treatment of psychiatric disorders. This chapter aims to discuss the effects of dietary nutrients on oxidative stress, neuroinflammation, mitochondrial dysfunction, and kynurenine pathway, which are significant mechanisms relevant to nutrients’ effects on brain health and disease. Furthermore, this chapter emphasizes the relevance of multiple possible pathways such as metabolic regulation, nutrigenomics, and gut-brain axis of nutrition to psychiatric diseases and therapeutic potential. Also, it provides insights into the effects of macronutrients such as AAs and fatty acids, and micronutrients, including vitamins and minerals, on psychiatric disorders like autism spectrum disorder, anxiety, attention deficit hyperactivity disorder, obsessive-compulsive disorder, depression, and bipolar depression. Particular attention will be given to the nexus between nutrients and schizophrenia. Taken together, dietary interventions may be repositioned as burgeoning, cost-effective therapeutic approaches in psychiatric disorders.KeywordsNutritionVitaminsGut-brain axisNutrigenomicsAutismDepressionSchizophreniaAttention deficit hyperactivity disorderObsessive-compulsive disorder
... Recent studies suggest that the genetic background of patients receiving ICIs could play a role in susceptibility to irAEs (21). Several single-nucleotide polymorphisms (SNPs) located in genes related to VitD metabolism have been linked to plasma 25(OH)D levels and immune disease (22). Given the immunoregulatory activity of VitD, we hypothesize a possible link between polymorphisms associated with VitD physiological disposition and ICI treatment outcomes. ...
Aim
Vitamin D (VitD) signaling has been increasingly investigated for its role in stimulating the innate and adaptive immune systems and suppressing inflammatory responses. Therefore, we examined the associations between VitD-related genetic polymorphisms, plasma 25-hydroxyvitamin D (25(OH)D), and the efficacy and safety of immune checkpoint inhibitors (ICIs).
Patients and methods
A total of 13 single-nucleotide polymorphisms (SNPs) in VitD metabolic pathway genes were genotyped in 343 cancer patients receiving ICI treatment using the MassARRAY platform. In 65 patients, the associations between plasma 25(OH)D levels and ICI treatment outcomes were investigated further.
Results
We found that the CYP24A1 rs6068816TT and rs2296241AA genotypes were significantly higher in patients who responded to ICIs. Furthermore, patients with higher plasma 25(OH)D levels had a better treatment response. The distribution of allele and genotype frequencies showed that three SNPs (rs10877012, rs2762934, and rs8018720) differed significantly between patients who had immune-related adverse events (irAEs) and those who did not. There was no statistically significant relationship between plasma 25(OH)D levels and the risk of irAEs.
Conclusion
In summary, our findings showed that genetic variations in the VitD metabolism pathway were associated with ICI treatment outcomes, and VitD supplementation may be useful in improving ICI treatment efficacy.
... VitD deficiency is a prevalence worldwide and can be caused by environmental factors such as diet, Sun exposure and stress (Dimakopoulos et al., 2019). Recently, accumulating evidence have reported a family cluster to VitD deficiency, which suggest the importance of genetic factors (Wang et al., 2010;Bahrami et al., 2018). This is mainly due to genetic variants involved in VitD metabolic pathways identified by whole-exome sequencing analysis (Alharazy et al., 2021). ...
Background: Uterine leiomyomas (ULs) is the most common gynecological benign tumor in women. Our previous study showed that the phenomenon of vitamin D deficiency existed in patients with ULs. However, the association of vitamin D anabolism-related gene polymorphisms and susceptibility to ULs was unclear.
Methods: Vitamin D anabolism-related gene polymorphisms in 110 patients with ULs and 110 healthy controls were detected by sequencing and the differences of the 92 SNPs were analyzed in the two groups via chi-square test. To verify the association between the significantly different SNPs and the risk of ULs, the SNPs were genotyped in another 340 patients and 340 healthy controls. Additionally, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) of ULs occurrence and the 95% confidence interval (CI), adjusting for age and BMI.
Findings: In sequencing samples, there were differences in DHCR7 rs1044482 C > T ( p = 0.008) and NADSYN1 rs2276360 G > C ( p = 0.025) between patients with ULs and healthy controls. DHCR7 rs1044482 was related to the susceptibility to ULs in validation samples (heterogeneous: adjusted OR = 1.967, p = 0.002; homogenous: adjusted OR = 2.494, p = 0.002; additive: adjusted OR = 1.485, p < 0.041; and dominant: adjusted OR = 2.084, p < 0.001). Stratified analysis further showed that the DHCR7 rs1044482 polymorphisms were associated with ULs risks in women over 40 and with 18.5–25.0 BMI. In contrast to the wild-type CG haplotype vectors, individuals with TC haplotypes had a higher risk of developing ULs.
Interpretation: The vitamin D anabolism-related gene DHCR7 rs1044482 C > T polymorphism was a risk factor of ULs, especially in patients over 40 with 18.5–25.0 BMI, while the relationship between NADSYN1 rs2276360 and ULs risk was not clear.
... Evidence about the involvement of other gene variations in vitamin D status, namely retinoid X receptors (RXR), calcium-sensing receptors (CASR), NPY, FOXA2, SSTR4, FGF23, CUBN, LRP2, and IVL, is limited [18,19]. ...
Vitamin D is essential for the normal mineralization of bones during childhood. Although diet and adequate sun exposure should provide enough of this nutrient, there is a high prevalence of vitamin D deficiency rickets worldwide. Children with certain conditions that lead to decreased vitamin D production and/or absorption are at the greatest risk of nutritional rickets. In addition, several rare genetic alterations are also associated with severe forms of vitamin-D-resistant or -dependent rickets. Although vitamin D3 is the threshold nutrient for the vitamin D endocrine system (VDES), direct measurement of circulating vitamin D3 itself is not a good marker of the nutritional status of the system. Calcifediol (or 25(OH)D) serum levels are used to assess VDES status. While there is no clear consensus among the different scientific associations on calcifediol status, many clinical trials have demonstrated the benefit of ensuring normal 25(OH)D serum levels and calcium intake for the prevention or treatment of nutritional rickets in childhood. Therefore, during the first year of life, infants should receive vitamin D treatment with at least 400 IU/day. In addition, a diet should ensure a normal calcium intake. Healthy lifestyle habits to prevent vitamin D deficiency should be encouraged during childhood. In children who develop clinical signs of rickets, adequate treatment with vitamin D and calcium should be guaranteed. Children with additional risk factors for 25(OH)D deficiency and nutritional rickets should be assessed periodically and treated promptly to prevent further bone damage.
... Both vitamin D status and obesity are under remarkable genetic influence, as reported by twin and family-based studies (35)(36)(37). Studies indicate that VDR gene polymorphisms are related to vitamin D levels, as VDR gene regulates vitamin D signaling pathways and vitamin D responsive genes, and may exert influence on adiposity and body composition (38)(39)(40)(41)(42)(43)(44)(45). ...
Vitamin D deficiency or insufficiency is common in obese people, with some studies suggesting that low vitamin D level might be an independent predictor of obesity. Thus, the purpose of the present randomized, double-blind, placebo-controlled study was to investigate the effect of oral spray vitamin D 3 3000 IU supplementation along with personalized weight-loss diet on obesity markers in overweight and obese Caucasians with vitamin d deficiency or insufficiency. The impact of vitamin D receptor (VDR) and adrenergic receptors (ADRs) genetic variants on vitamin D levels and weight loss diet outcomes was also investigated. After signing informed consent, a total of 125 eligible volunteers were randomly assigned into vitamin D (vitamin D 3 3000 IU/d oral spray supplementation, n = 76) or placebo (xylitol, water, mint, n = 49) group following a weight loss program (600 calories less than the total energy expenditure of each volunteer) for 3 months. Fat mass, BMI, REE and 25(OH)D serum level were monitored on baseline and each month. DNA samples were extracted from buccal swabs and genotyped for the rs2228570 (VDR), rs1544410 (VDR), rs731236 (VDR), rs1800544 (ADRA2A), rs1801252 (ADRB1), rs1042713 (ADRB2), and rs4994 (ADRB3) polymorphisms. Statistical analysis was performed using SPSS package (v.23). Between group comparisons revealed significant improvement in serum 25(OH)D level and greater reduction in weight, BMI and fat percentage in the vitamin D group compared to placebo group (p < 0.05). In the vitamin D group, carriers of the rs2228570 T allele tended to have greater vitamin D level improvement compared with the homozygous C allele (p = 0.067). Furthermore, heterozygous (CT) for the rs731236 tended to have lesser weight loss (p = 0.068) and for the rs1042713, a lower decline in fat percentage was observed for homozygous AA carriers compared to the heterozygous (p = 0.051). Xenos et al. Vitamin D Supplementation and Weight Loss In the control group, differences in weight loss (p = 0.055) and BMI (p = 0.045) were observed between rs1544410 AA and GG homozygous. In conclusion, vitamin D oral spray supplementation seems to improve vitamin D status and decrease obesity markers during a weight-loss intervention in overweight/obese Caucasians with vitamin D deficiency or insufficiency. Also, the results of the present study indicate that VDR and ADRs genetic polymorphisms seem to influence vitamin D supplementation response and obesity markers.
... In the present study, no significant relationship between the seven VDBP SNPs above and plasma VD levels was observed either after adjustment for age, gender, and metabolic factors. Such inconsistent results may be explained by backgrounds of sun exposure, season, dietary intake, and skin color [61]. ...
Introduction:
Vitamin D binding protein (VDBP) is correlated with non-alcoholic fatty liver disease (NAFLD) through the biological functions of regulating plasma vitamin D (VD) level and the inflammatory process.
Objective:
This study aims to investigate the effects of VD level and VDBP gene polymorphisms on the risk of NAFLD in a Chinese population.
Methods:
Plasma 25-hydroxyvitamin D3 [25(OH)D3] levels were measured and seven VDBP candidate genetic variants (rs222020, rs2282679, rs4588, rs1155563, rs7041, rs16847024, rs3733359) were genotyped among participants in this case-control study. The control group was frequency-matched to NAFLD case group by age and gender. Correlation analysis and multiple linear regression were used to screen determinants of 25(OH)D3 levels. Multivariable unconditional logistic regression was performed to estimate odds ratio (OR) and 95% confidence interval (95% CI). The prediction capability of models containing independent factors was estimated by the area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test.
Results:
Age, BMI and TG were independent factors influencing VD levels. Participants with low VD levels had significantly higher prevalence of NAFLD compared to subjects with normal VD levels (P < 0.001). A low VD level contributed to increased risk of NAFLD, independent of metabolic factors known to affect VD levels (adjusted OR = 2.282, 95% CI = 1.422-3.661, P = 0.001). Logistic regression analysis showed that individuals carrying rs7041-G allele had a significantly decreased risk of NAFLD occurrence compared to T allele (additive model: adjusted OR = 0.814, 95% CI = 0.713-0.929, P = 0.002; codominant model: adjusted OR = 0.623, 95% CI = 0.449-0.866, P = 0.005), after adjusting for age, gender, and overweight. Stratification by multiple metabolic disorders did not alter this relationship. Moreover, we developed a simple model including age, gender, metabolic disorders and VDBP SNP to assess NAFLD risk, an AUC of which being 0.817, significantly higher than the model not included VDBP SNP, with Hosmer-Lemeshow test fitting well (P = 0.182).
Conclusions:
Low plasma VD levels may increase susceptibility to NAFLD, while rs7041-G allele in VDBP contributed to a decreased NAFLD risk among Chinese population. The VDBP variant significantly improved the capability for NAFLD risk assessment, which could be used for early screening and management of NAFLD.
... On the other hand, the above mentioned "vitamin D tool" genes coding VDR, CYP2R1, CYP27A1 and CYP24A1 tend themselves to be epigenetically regulated [13]. Promoter regions of these genes span the Cytosine-phosphate-Guanine (CpG) dinucleotide islands and thus can be silenced by DNA methylation [13,14]. It is known that vitamin D deficiency is prevalent in RA patients, is associated with higher disease activity and the level appears to be significantly lower compared to healthy controls [15,16]. ...
Background:
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex etiopathogenesis launched by multiple risk factors, including epigenetic alterations. RA is possibly linked to vitamin D that is epigenetically active and may alter DNA methylation of certain genes. Therefore, the study aimed to evaluate the relationship between DNA methylation status of vitamin D signaling pathway genes (VDR, CYP24A1, CYP2R1), vitamin D level and associations with RA.
Materials and methods:
Totally 76 participants (35 RA patients and 41 healthy controls) were enrolled from a case-control vitamin D and VDR gene polymorphisms study regarding age and vitamin D concentration. CpG islands in promoter regions of the VDR, CYP24A1, CYP2R1 genes were chosen for DNA methylation analysis by means of pyrosequencing. Chemiluminescent microplate immunoassay was used to assess 25(OH)D serum levels. RA clinical data, i.e. the disease activity score C-reactive protein 28 (DAS28 - CRP) as well as patient-reported outcome questionnaires were recorded.
Results:
The study showed similar methylation pattern in the promoter regions of vitamin D pathway genes in RA and control group with p>0.05 (VDR gene 2.39% vs. 2.48%, CYP24A1 gene 16.02% vs. 15.17% and CYP2R1 2.53% vs. 2.41%). CYP24A1 methylation intensity was significantly higher in compare to methylation intensity of VDR and CYP2R1 genes in both groups (p<0.0001). A tendency of higher vitamin D concentration in cases having methylated VDR (57.57±28.93 vs. 47.40±29.88 nmol/l), CYP24A1 (53.23±26.22 vs. 48.23±34.41 nmol/l) and CYP2R1 (60.41±30.73 vs. 44.54±27.63 nmol/l) genes and a positive correlation between VDR, CYP2R1 methylation intensity and vitamin D level in RA affected participants was revealed (p>0.05). A significantly higher CYP24A1 methylation intensity (p=0.0104) was detected in blood cells of vitamin D deficient (<50 nmol/l) RA patients vs. vitamin D deficient controls.
Conclusions:
Our data suggests some indirect associations between DNA methylation status of vitamin D pathway genes and vitamin D level in RA.
... Curcumin (CUR) is a bioactive polyphenolic ingredient derived from the spice turmeric, acquired from the root of the Curcuma longa plant, a member of the Zingiberaceae family. CUR has a wide range of reported protective pharmacological properties such as antiinflammatory, antioxidant, anti-neoplasm, neuro-and cardio-protective, immunomodulatory, analgesic, lipidlowering and antidepressant effects [13][14][15][16][17]. CUR can interact with multiple molecular targets and modulate their activity including enzymes, inflammatory cytokines, transcription factors, growth factors, hormones, receptors, adipokines and various signaling cascades [16,17]. ...
Background
Vitamin D has an established role in female reproduction. There is also evidence for an association between vitamin D levels and menstrual problems such as premenstrual syndrome (PMS) and dysmenorrhea. Curcumin, is a bioactive polyphenol constituent of turmeric, that can potentially interact with vitamin D receptors and its molecular targets. This study evaluated the effects of curcumin on vitamin D levels in young women with PMS and dysmenorrhea.
Methods
In this randomized, triple-blind, placebo-controlled trial, women with PMS and dysmenorrhea were divided randomly into experimental and control groups to receive one capsule (500 mg of curcuminoid+ 5 mg piperine, or placebo) daily, from approximately 7 days before until 3 days after menstruation for three consecutive menstrual cycles. Serum vitamin D levels, renal function, and liver enzymes were also measured before and after intervention.
Results
A total of 76 subjects (38 in each group) were recruited into the trial. Curcumin significantly increased the median (IQR) serum levels of vitamin D [from 12.8 ng/ml (7.0–24.6) to 16.2 ng/ml (6.4–28.8); P = 0.045], compared with placebo [from 18.6 ng/ml (2.2–26.8) to 21.3 ng/ml (5.2–27.1); P = 0.17]. Serum levels of aspartate aminotransferase and direct bilirubin were reduced by the end of trial in the curcumin group (p < 0.05), but did not change significantly in the control group (p > 0.05). Finally, no significant differences in levels of fasting blood glucose were detected between curcumin and placebo groups.
Conclusion
Curcumin supplementation in women with PMS and dysmenorrhea led to a significant improvement of vitamin D, liver function enzyme test, but did not affect blood glucose.
Trial registration
The trial was registered on Iranian Registry of Clinical Trials registry (Trial ID: IRCT20191112045424N1 on 23 January 2020; available at https://www.irct.ir).
... 21 Moreover, variations in the allele frequency of Chinese and Thailand's populations may partly explain the discrepancy, as the allele frequency of rs4588 in Chinese differs dramatically from other populations, when assessed by the 1000 Genomes Project Phase 3 sequence data in NCBI (C = 0.739 in East Asian; C = 0.697 in South Asian). In the meantime, correlation analysis has only focused on the relationship of vitamin D levels and GC gene polymorphisms 22,23 or between vitamin D contents and MetS. 24 Future studies with much more cases are needed to confirm the associations between GC gene variants and MetS risk among various populations. ...
Background:
GC (group-specific component globulin) encoding VDBP (Vitamin D binding protein) polymorphisms have been associated with susceptibility to some diseases such as diabetes, obesity, osteoporosis, and polycystic ovary syndrome, but the evidence for metabolic syndrome (MetS) in the Chinese rural population is inconclusive. Therefore, we investigated the relationship between GC variants (rs7041, rs4588, rs2282679, and rs705117) and MetS risk as well as VDBP levels in the Chinese rural population.
Patients and methods:
The participants (range of age: 20-90 years) of this case-control study were recruited from the northern Chinese Han rural population. We matched 445 MetS cases with non-MetS controls in a 1:1 ratio by sex, age (within 5 years). Real-time PCR technology was carried out by TaqMan assays to examine the four variants of rs7041, rs4588, rs2282679, and rs705117 within the GC gene. To identify the association of GC gene polymorphisms with MetS, we calculated ORs using a conditional logistic regression model adjusted for potential confounding factors.
Results:
We observed inverse associations of CA and AA genotypes of rs4588 with risk of MetS (OR = 0.678, 95% CI 0.505-0.910, P = 0.010; 0.603, 95% CI 0.373-0.973, P = 0.039, respectively) compared with carriers of CC genotype. A similar relationship was also found between rs2282679 and MetS, showing that carrying AC genotype of rs2282679 can decrease the risk of MetS (OR = 0.683, 95% CI 0.509-0.917, P = 0.011) compared with carriers of AA genotype. The results of correlation analysis between MetS components and GC polymorphisms showed that the ORs of AA genotype of rs4588 with high level of TG (triglycerides) and low level of HDL-C (high-density lipoprotein cholesterol) were 0.473 (95% CI 0.245-0.911, P = 0.025) and 0.268 (95% CI 0.117-0.615, P = 0.002), respectively; the ORs of CC genotype of rs2282679 with high level of TG and low level of HDL-C were 0.428 (95% CI 0.217-0.842, P = 0.014) and 0.263 (95% CI 0.110-0.628, P = 0.003), respectively. However, there was no significant association between the concentration of VDBP and MetS risk.
Conclusion:
Among the Chinese rural population, GC polymorphism was associated with lower metabolic syndrome susceptibility, which might be through affecting blood lipid levels (TG and HDL-C).
... Nevertheless, whether fat compartments (visceral and subcutaneous) are differently associated with vitamin D status is still a matter of debate 15,16 . The isolated influence of variation in vitamin D pathway genes or its interaction with environmental factors may also play a role in determining vitamin D status 17,18 . Several single nucleotide polymorphisms (SNPs) in genes involved in the synthesis (eg., DHCR7), transportation (eg., GC), and activation/inactivation (eg., CYP2R1 and CYP24A1) of vitamin D have been associated with serum 25(OH)D concentration 19,20,21,22 . ...
This study aims to investigate factors associated with serum 25-hydroxyvitamin D [25(OH)D] concentration in Brazilian adults considering sociodemographic and lifestyle factors, as well as vitamin D-related single nucleotide polymorphisms (SNPs). This is a cross-sectional study (n = 491; 34-79y; 251 women), nested within a prospective cohort (Pró-Saúde Study). Associations between serum 25(OH)D and sociodemographic characteristics, diet, use of supplement, physical activity, season of blood collection, body fat, skin type, sun exposure index, and SNPs CYP2R1-rs10741657 and GC-rs2282679 were explored by multiple linear regression. The prevalence of serum 25(OH)D < 50nmol/L was 55%. Serum 25(OH)D was lower among women (β = -4.38; 95%CI: -8.02; -0.74), those with higher visceral fat (β = -4.02; 95%CI: -5.92; -2.12), and those with AC and CC genotypes for GC-rs2282679 (β = -6.84; 95%CI: -10.09; -3.59; β = -10.63; 95%CI: -17.52; -3.74, respectively). Factors directly associated with serum 25(OH)D included summer (β = 20.14; 95%CI: 14.38; 25.90), intermediate skin type (β = 6.16; 95%CI: 2.52; 9.80), higher sun exposure (β = 0.49; 95%CI: 0.22; 0.75), vitamin D intake (β = 0.48; 95%CI: 0.03; 0.93), and physical activity (β = 4.65; 95%CI: 1.54; 7.76). Besides physical activity, diet, and sun exposure, non-modifiable factors, such as GC genotypes must be considered when evaluating vitamin D insufficiency in mixed-race populations. Moreover, high visceral fat in association with poorer vitamin D status deserve attention given that both conditions are unfavorably related with chronic and acute health outcomes.
... Vitamin D is a liposoluble molecule and can be stored in fatty tissues, reducing at the same time the circulating fraction of the molecule [5]. Finally, many genetic alterations can affect the production, transport, or binding of vitamin D metabolites [6]. ...
Sunlight is the main source of vitamin D. Almost 80% of vitamin D3 is produced in the skin. The region of Draa Tafilalet benefits from long daily sunshine time. As such, vitamin D deficiency should be low in this region. However, dressing habits can highly influence vitamin D status. This study aimed to evaluate sun exposure and its relation to vitamin D status among the general population in the region of Draa-Tafilalet, Morocco. Clinical, biological, and sociodemographic data were obtained from 331 adults visiting local healthcare units during the summers of 2019 and 2020. Plasma 25(OH)D 2 /D3 was measured by immunofluorescence. The prevalence of vitamin D deficiency was 37.5%, while Vitamin D insufficiency represented 56.5%. Most of the studied population (76.4%) had restricting dressing habits and exposed only their faces. statistic tests showed a correlation of vitamin D levels with daily sun exposure (r= 0.308, p<0.001), dressing habits (p<0.001), age (r= -0.141, p=0.01), sex (p<0.001), physical activity level (p=0.003), and BMI (r= -0.298, p<0.001). The study showed a high prevalence of vitamin D deficiency in this region. Similarly, it exposed the effects of restricting clothes and low daily sun exposure on vitamin D status.
... Blood samples were available from baseline for genetic analysis. We considered 4 common single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism and serum 25(OH)D that had previously been suggested to be important in determining vitamin D concentration [17,23]. Genotyping was undertaken by LGC Genomics (Hoddeston, UK) using KASP-competitive allele-specific polymerase chain reaction. ...
br/>Introduction Several studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population.
Methods Participants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9–12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as “a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene”.
Results 820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8–66.5) and 65.5 (63.3–67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0–63.0) nmol/L and 41.3 (29.8–53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p < 0.001). The greatest variance in a model of vitamin D status that included the four SNPs measured, season, and whether participants reported taking vitamin D supplements was explained by season of assay (17.9% men; 15.8% women). Higher femoral neck BMD was observed in men with higher baseline vitamin D status, after adjustment for age, season, BMI, smoker status, alcohol consumption, physical activity and social class (p = 0.01). Associations between 25(OH)D and BMD in women were not statistically significant in this population. There were no associations between circulating 25(OH)D and radiographic knee OA at either time point after adjustment for confounders and for duration of follow-up.
Conclusion Circulating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.
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... For example, 1,25(OH) 2 D 3 improves glucose metabolism via the SIRT1/IRS1/ GLUT4 signaling cascade in C2C12 myotubes [17]. In addition, vitamin D is indirectly related to oxidative stress [18], sub-inflammation [19], and epigenetics [20]. ...
Background
The aim of the study was to explore the relationship between vitamin D status and islet function in patients with type 2 diabetes mellitus.
Methods
The participants were recruited from Hebei General Hospital. Basic characteristics and blood indicators were collected after fasting overnight. The data were analyzed statistically using SPSS 22.0. Analysis of variance, a nonparametric test, or a trend Chi-square test was used for the comparisons. The association between 25-hydroxy vitamin D and modified homeostasis model assessment-β was assessed using multivariate ordinal logistic regression.
Results
One hundred seventy-four patients aged 26 to 79 years with type 2 diabetes mellitus were included in this study. Patients with vitamin D deficiency had a lower modified homeostasis model assessment-β level compared with those without vitamin D deficiency. There were differences in body mass index, diabetes course, glycosylated hemoglobin, fasting blood glucose, fasting blood C-peptide, triglyceride, and 25-hydroxy vitamin D among different modified homeostasis model assessment-β groups based upon the tertiles. 25-hydroxy vitamin D, as continuous or categorical variables, was positively related to modified homeostasis model assessment-β whether or not cofounding factors were adjusted.
Conclusion
There is an association between increased 25-hydroxy vitamin D levels and improvement in modified homeostasis model assessment-β function in patients with type 2 diabetes mellitus.
Trial registration
Cross-sectional trails ChiCTR2000029391 , Registration Date: 29/01/2020.
... Furthermore, dietary sources of Vit D are limited and the obesity epidemic in the Europe, which is also related to poorer dietary choices, can worsen its deficiency [51]. Additionally, vegetarianism and veganism [52] and chronic diseases such as kidney disease [53,54], liver disease [55], malignancies [56], and genetic and epigenetic factors [57] can influence Vit D concentration. ...
Objective: Coronavirus disease 2019 (COVID-19) has emerged as a pandemic, affecting nearly 180 million people worldwide as of June 22nd, 2021. In previous studies, the association between the mean Vitamin D (Vit D) concentration of each country and COVID-19 infection and mortality rate in European countries was examined. The aim of this study was to critically evaluate the relationship between Vit D mild and severe deficiency prevalence in each country and COVID-19 infection, recovery, and mortality using updated data and a different methodological approach.
Research Methods & Procedures: Information on Vit D concentration/deficiency for each country was retrieved through literature search. As of June 22nd, 2021, COVID-19 infections and mortalities per one million population as well as total recoveries were obtained. The association between Vit D deficiency and COVID-19 infection, recovery, and mortality were explored using correlation coefficients and scatterplots.
Results: Non-significant correlations were observed between the number of COVID-19 infections (r=0.363; p=0.116), and recoveries (r=0.388, p=0.091) with the prevalence of mild Vit D deficiency (<50 nmol/L). Similarly, non-significant correlations were observed between COVID-19 infections (r=0.215, p=0.392) and recoveries (r=0.242, p=0.332) with the prevalence of severe Vit deficiency (<30 nmol/L). Significant correlations were found between COVID-19 mortality and prevalence of both mild Vit D deficiency (<50 nmol/L), (r=0.634, p=0.003) and severe Vit D deficiency (<30 nmol/L) (r=0.538, p=0.021 and COVID-19 mortality rates.
Conclusions: Prevalence of both mild and severe Vit D deficiency was not associated with the number of infections of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to face COVID-19.
... Advances in the methodology of large-scale genetic association studies along with international collaboration have identified four single-nucleotide polymorphisms (SNPs) from four genes that influence 25(OH) D concentrations [17,18]. Genetic variants of synthesis genes DHCR7/NAD-SYN1 (7-dehydrocholesterol reductase) and CYP2R1 (25hydroxylase) affect the synthesis of 25(OH)D; the transport gene GC (group-specific component) encodes the vitamin D-binding protein, and the catabolism gene CYP24A (24hydroxylase) is involved in the clearance of 25(OH) D [19]. ...
Background
Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China.
Methods
A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017–2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations.
Results
Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06–1.61) and of T2D of 1.32 (1.08–1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24–1.79) and of T2D of 1.47 (1.12–1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29–1.85) and of T2D of 1.54 (1.27–1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02–1.45) for T2D and 1.14 (95%CI: 1.03–1.43) for DBP.
Conclusions
This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.
... In addition, there are physiological, pathological, and lifestyle factors affecting 25(OH)D levels such as aging, obesity, liver and kidney diseases, and inadequate exposure to sunlight (Holick, 2004(Holick, , 2007Tsiaras and Weinstock, 2011;Hyppönen and Boucher, 2018). Among other significant factors influencing 25(OH)D levels are the genetic factors with the heritability of circulating 25(OH)D levels predicted to be between 23 and 80% (Bahrami et al., 2018), primarily as single-nucleotide polymorphisms (SNPs) in genes involved in the vitD metabolic pathway (Ahn et al., 2010;McGrath et al., 2010;Wang et al., 2010;Jolliffe et al., 2016). ...
Background
Numerous research studies have found an association between vitamin D (vitD) status and single-nucleotide polymorphisms (SNPs) in genes involved in vitD metabolism. It is notable that the influence of these SNPs on 25-hydroxyvitamin D [25(OH)D] levels might vary in different populations. In this study, we aimed to explore for genetic variants in genes related to vitD metabolism in families with vitD deficiency in Saudi Arabia using whole-exome sequencing (WES).
Methods
This family-based WES study was conducted for 21 families with vitD deficiency ( n = 39) in Saudi Arabia. WES was performed for DNA samples, then resulting WES data was filtered and a number of variants were prioritized and validated by Sanger DNA sequencing.
Results
Several missense variants in vitD-related genes were detected in families. We determined two variants in low-density lipoprotein 2 gene (LRP2) with one variant (rs2075252) observed in six individuals, while the other LRP2 variant (rs4667591) was detected in 13 subjects. Single variants in 7-dehydrocholesterol reductase (DHCR7) (rs143587828) and melanocortin-1 receptor (MC1R) (rs1805005) genes were observed in two subjects from two different families. Other variants in group-specific component (GC), cubilin (CUBN), and calcium-sensing receptor (CASR) gene were found in index cases and controls. Polymorphisms in GC (rs9016) and CASR (rs1801726) were found in the majority of family cases (94 and 88%), respectively.
Conclusion
In vitD-deficient families in Saudi Arabia, we were able to detect a number of missense exonic variants including variants in GC (rs9016), CUBN (rs1801222), CASR (rs1801726), and LRP2 (rs4667591). However, the existence of these variants was not different between affected family members and non-affected controls. Additionally, we were able to find a mutation in DHCR7 (rs143587828) and a polymorphism in LRP2 (rs2075252), which may affect vitD levels and influence vitD status. Further studies are now required to confirm the association of these variants with vitD deficiency.
... We also looked at the potential relationship between calcium and vitamin D intake and BMD data that was available for 121 participants in the present dataset, but we did not find any significant associations between BMD and calcium or vitamin D intake. These findings are not entirely surprising considering that vitamin D status is influenced by several factors including sun exposure, genetics [31], and obesity [32]. Even though vitamin D intake by study participants did not meet recommendations, vitamin D status may have been adequate, which would also support the normal BMD data described here. ...
The purpose of this cross-sectional study was to examine the relationship between diet and anthropometric measures in postmenopausal women. Data collected from 937 women enrolled in the Minnesota Green Tea Trial (NTC00917735) were used for this analysis. Dietary intake and health-related data were collected via questionnaires. Body weight, height, and waist circumference (WC) were measured by the study staff. The mean age of participants was 59.8 years and mean WC was 83 cm. Approximately 30% of the participants had WC greater than 88 cm. Healthy Eating Index-2015 score was 72.6 and the Dietary Inflammatory Index score was 0. Intakes of whole grains, dairy, protein, sodium, and saturated fat did not meet the dietary guidelines. Only 12.5% consumed the recommended daily amount of calcium (mean intake = 765 mg/day). When calcium supplements were considered, only 35.2% of the participants had adequate intakes, even though 68.9% reported taking a calcium supplement. We found that age and number of medications taken were significantly associated with waist circumference (p = 0.005). Women who reported taking two or more medications had greater WC (85 cm) compared to women who reported not taking any medications (82.2 cm), p = 0.002. Our findings suggest that achieving adequate calcium and vitamin D intake may be challenging to postmenopausal women.
... This nuclear receptor is expressed in many tissues, showing the wide range of effects of vitamin D in human metabolism [18]. Mutation and polymorphism in genes involved in vitamin D metabolism, catabolism, DBP, or VDR might be associated with altered vitamin D status and disease [19,20]. ...
Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.
... In the last two decades, scientists elucidated genetic and epigenetic factors that impact vitamin D abundance, these include single nucleotide polymorphisms (SNPs) in different genes contributing to the vitamin D pathway [3,11]. Namely, 7-dehydrocholesterol reductase (DHCR7), an enzyme encoded by the DHCR7 gene, is a rough endoplasmic reticular/nuclear transmembrane enzyme that mediates cholesterol synthesis from 7-dehydrocholesterol [12]. ...
Introduction
Vitamin D deficiency has been linked to cardiovascular pathologies including acute coronary syndrome (ACS). Polymorphisms in vitamin D associated genes have been confounding to vitamin D serum levels and pathological predispositions. 7-hydrocholesterol is a common precursor in cholesterol and vitamin D synthesis. DHCR7/NADSYN1 genetic locus expresses 7-hydrocholesterol reductase (DHCR7), an enzyme that recruits 7-hydrocholesterol in cholesterol biosynthesis, and NAD synthetase 1 (NADSYN1), which participates in the hydroxylation of 25 hydroxyvitamin D.
Aim
This study aims to correlate two polymorphisms in the DHCR7/NADSYN1 genetic locus with levels of circulatory vitamin D and the presentation of ACS in an Egyptian population.
Methods
In a case control study, 189 ACS patients and 106 healthy control subjects were genotyped for SNPs rs11606033 of the DHCR7 gene and rs2276360 of the NADSYN1 gene using the amplification-refractory mutation system (ARMS). The levels of 25(OH)D2 and 25(OH)D3 were measured using an in-house developed and validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) based protocol.
Results
ACS patients have significantly lower levels of circulating vitamin D in comparison to healthy controls. Allele A of the DHCR7 polymorphism was found to correlate with serum vitamin D deficiency and incidence of ACS classes: NSTEMI, STEMI and unstable angina, when compared to allele G. On the other hand, the NADSYN1 polymorphism rs2276360 correlated with serum 25(OH)D3 deficiency. Yet, no significant correlation was found with incidences of ACS.
Conclusion
We conclude that rs11606033, which is an intronic SNP between exon 4 and exon 5 of the DHCR7 gene, influences vitamin D serum abundance and more importantly ACS incidence.
... 25 in the Europe, which is also related to poorer dietary choices, can worsen its deficiency. 53 Additionally, chronic diseases such as kidney disease, 54,55 liver disease, 56 malignancies 57 and genetic-epigenetic factors 58 can influence Vit D status. ...
Background: COVID-19 has emerged as a global pandemic, affecting nearly 104 million people worldwide as of February 4th 2021. In previous published studies, the association between the mean Vit D status of each country and COVID-19 infection rate, and mortality among the adult population in European countries was examined. The aim of this study was to re-examine the relationship between the Vit D status of each country and COVID-19 infection, recovery, and mortality using updated data and a different methodological approach.
Methods: Information only form the last decade on Vit D concentration/deficiency for each country was retrieved through literature search on PubMed database. As of February, 4th 2021, COVID-19 infections and mortalities per one million population as well as total recoveries were extracted from the Worldometer website. The association between vitamin D deficiency and COVID-19 infection, recovery, and mortality were explored using correlation coefficients and scatterplots.
Results: The prevalence of vitamin D deficiency among European countries ranged from 6.0 (Finland) to 75.5% (Turkey), with several countries facing more than 50% of vitamin D deficiency among their population. Non-significant correlations were observed between the number of COVID-19 infections (r=0.190; p=0.374), recoveries (rs=0.317, p=0.131), and mortalities (r=0.129; p=0.549) per one million population, with the prevalence of vitamin D deficiency.
Conclusions: Prevalence of vitamin D deficiency was not significantly associated with either number of infections, recoveries or mortality rate of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to face COVID-19.
... Biomarkers of oxidative stress and inflammation may be found at higher levels in hemodialysis patients, along with increased risk for CVD, death, and other uremia-related comorbidities (1,43,44), and this may result from uremia and dialysis itself. Vitamin D can modulate important pathways of the immune system, such as the tolllike receptor signaling pathway, suppressor of cytokine signaling 1 pathway, and NF-kB pathway in human macrophages (45)(46)(47). Recently, Brito et al. described a favorable effect of vitamin D supplementation on the levels of TLR-4, MCP-1, and CAMP in monocytes treated with uremic serum (42). ...
OBJECTIVES: This study aimed to evaluate the potential anti-inflammatory effects of vitamin D supplementation under uremic conditions, both in vivo and in vitro, and its effects on the parameters of mineral metabolism. METHODS: Thirty-two hemodialysis patients were randomly assigned to receive placebo (N=14) or cholecalciferol (N=18) for six months. Serum levels of calcium, phosphate, total alkaline phosphatase, intact parathyroid hormone (iPTH), and vitamin D were measured at baseline and after three and six months. The levels of fibroblast growth factor-23 (FGF-23), interleukin-1β (IL-1β), and high-sensitivity C-reactive protein (hs-CRP) were also measured at baseline and at six months. Human monocytes were used for in vitro experiments and treated with cholecalciferol (150 nM) and uremic serum. Cell viability, reactive oxygen species (ROS) production, and cathelicidin (CAMP) expression were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dichloro-dihydro-fluorescein diacetate assay, and real time-quantitative polymerase chain reaction, respectively. RESULTS: Both patient groups were clinically and biochemically similar at baseline. After six months, the levels of vitamin D and iPTH were higher and lower, respectively, in the cholecalciferol group than in the placebo group (p
... Advances in methodology of large-scale genetic association studies and international collaboration have identi ed four single nucleotide polymorphisms (SNPs) from four genes that in uence 25(OH)D concentration, which represent circulating vitamin D levels [17,18]. Genetic variants of synthesis genes DHCR7/NADSYN1 (7-dehydrocholesterol reductase) and CYP2R1 (25-hydroxylase) affects the synthesis of 25(OH)D, transport gene GC (group-speci c component) encodes the vitamin D binding protein, and catabolism gene CYP24A (24-hydroxylase) is involved in the clearance of 25(OH)D [19]. ...
Background: Vitamin D deficiency is common around the world, but the association between vitamin D deficiency with metabolic syndrome and its associated diseases is unclear.
Methods: A subset of 2393 participants from the Nantong Chronic Diseases Study (NCDS) of 2017-2018 were included in this study.The risk of MS and its associated diseases from low vitamin D levels were assessed by genetic scores using two 25(OH)D synthesis single nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657), one transport SNP (GC-rs2282679) and one catabolism SNP (CYP24A1-rs6013897).
Results: Odds Ratios (ORs) for decreased risk of MS and type 2 diabetes (T2D) was 0.73 and 0.79 in the deficient, 0.53 and 0.67 in the insufficient, and 0.54 and 0.60 in the sufficient categories of serum vitamin D levels, respectively. Mendelian randomization analysis showed per 25nmol/L higher genetically instrumented serum 25(OH)D concentration using the two synthesis SNPs: DHCR7+CYP2R1 genes, associated with a 7% lower risk of T2D. The highest tertile vs the lowest tertile of genetic scores using the three SNPs of DHCR7+CYP2R1+GC genes showed a 10% lower risk of T2D. Also, the group with higher genetic scores among these two and three SNPs were both associated with lower risk of abnormal diastolic blood pressure (DBP) (P=0.0162 and 0.0045 respectively).
Conclusions: Our Mendelian randomization analysis showed no genetic evidence for a causal role of lower vitamin D level in the development of MS, but showed a causal role in the development of T2D and DBP in middle-aged and elderly participants from rural China.
... In addition, vitamin D is a controller of chronic inflammation and oxidative stress (14) closely related to the occurrence and development of many chronic conditions such as cardiovascular disease and other degenerative processes (15). The potential mechanisms by which vitamin D exert the biological actions are linked to the key redox agent glutathione and regulated by epigenetic modifications (16)(17)(18). ...
Background:
Vitamin D has gone from being just one vitamin to being an important prohormone with multiple effects on different tissue types. The mechanism of action of the active form or calcitriol is mediated by the intracellular vitamin D receptor (VDR). The interaction of the VDR with calcitriol modulates the expression of target genes involved in cell proliferation and cytokine production. Several studies have explored the effects of vitamin D deficiency in inflammatory disorders. Furthermore, some mutations in the VDR can affect its functionality. The focus of this study was to explore associations between VDR single nucleotide polymorphisms (SNPs) and markers of inflammation and oxidative stress in vitamin D sufficient children.
Methods:
This is a cross-sectional study of a Caucasian Spanish population including 155 healthy children (87 males, 68 females) aged 10 to 14 years. FokI, ApaI and TaqI SNPs of the VDR gene were genotyped. Routine biochemistry, serum levels of interleukin-6, tumor necrosis factor-α, interferon-γ, 8-isoprostaglandin F2α and nitrates were determined.
Results:
The homozygous major allele AA in the FokI SNP was associated with increased levels of high-density lipoprotein cholesterol in a recessive inheritance mode (P=0.025). The minor allele A of ApaI was significantly associated with decreased serum tumor necrosis factor-α and 8-isoprostaglandin F2α in an additive mode (P=0.016 and P=0.020 respectively). No significant associations were observed between the TaqI SNP and any of the parameters evaluated. Haplotype analysis confirmed the significance of the relationships between ApaI and FokI SNPs and parameters associated with inflammation and oxidative stress.
Conclusions:
Genetic variations of VDR are associated with subtle changes in metabolic, inflammatory and oxidative stress markers. These results may provide a better understanding of the relationships between vitamin D and these clinical parameters.
... 35 FokI is located on the second exon of the VDR gene, and the FokI polymorphism creates an alternative transcription start site, leading to a VDR protein with 3 amino acids shorter than the one without the polymorphism. 36 This change consequently influences its activity, thereby lowering its transcriptional activation effectiveness and altering the functional properties of the receptor, 37 which may partly explain these findings. ...
Purpose:
To investigate the association between vitamin D receptor (VDR) gene polymorphisms and vitamin D deficiency, overweightness/obesity, and metabolic syndrome (MetS) in a cohort of Han children residing in Hangzhou, China.
Patients and methods:
This study assessed 106 overweight/obese and 86 healthy (control) children. Five single-nucleotide polymorphisms (SNPs) in the VDR gene, namely, TaqI (rs731236 T > C), ApaI (rs7975232 C > A), BsmI (rs1544410 G > A), FokI (rs2228570 G >A), and Cdx2 (rs11568820 G > A), were genotyped by sequencing the total polymerase chain reaction products. The distributions of different genotypes and alleles were compared among different groups.
Results:
The serum 25-hydroxyvitamin D (25(OH)D) concentration was significantly lower in overweight/obese children, while the AA genotype of ApaI SNP exhibited higher frequencies in the overweight/obese group than in the control. Furthermore, children with the ApaI AA genotype showed higher levels of Glu-60min, Glu-90min, Glu-120min and triglyceride. The AA genotype of FokI SNP was significantly associated with MetS. However, no association was observed between the five VDR SNPs and the risk of vitamin D deficiency.
Conclusion:
VDR ApaI polymorphisms appear to be correlated with overweightness/obesity and glucose intolerance. FokI polymorphisms may be linked to a higher susceptibility toward MetS in Chinese children.
... Second, vitamin D levels may be related to genetic factors. Vitamin D metabolic and vitamin D receptor gene variants that were shown to be associated with ASD risk might influence vitamin D status [55][56][57]. The use of drugs like antiepileptic drugs might also cause vitamin D loss [58]. ...
The association between vitamin D status and autism spectrum disorder (ASD) is well-investigated but remains to be elucidated. We quantitatively combined relevant studies to estimate whether vitamin D status was related to ASD in this work. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched to include eligible studies. A random-effects model was applied to pool overall estimates of vitamin D concentration or odds ratio (OR) for ASD. In total, 34 publications involving 20,580 participants were identified in this present study. Meta-analysis of 24 case–control studies demonstrated that children and adolescents with ASD had significantly lower vitamin D concentration than that of the control group (mean difference (MD): −7.46 ng/mL, 95% confidence interval (CI): −10.26; −4.66 ng/mL, p < 0.0001, I2 = 98%). Quantitative integration of 10 case–control studies reporting OR revealed that lower vitamin D was associated with higher risk of ASD (OR: 5.23, 95% CI: 3.13; 8.73, p < 0.0001, I2 = 78.2%). Analysis of 15 case–control studies barring data from previous meta-analysis reached a similar result with that of the meta-analysis of 24 case–control studies (MD: −6.2, 95% CI: −9.62; −2.78, p = 0.0004, I2 = 96.8%), which confirmed the association. Furthermore, meta-analysis of maternal and neonatal vitamin D showed a trend of decreased early-life vitamin D concentration in the ASD group (MD: −3.15, 95% CI: −6.57; 0.26, p = 0.07, I2 = 99%). Meta-analysis of prospective studies suggested that children with reduced maternal or neonatal vitamin D had 54% higher likelihood of developing ASD (OR: 1.54, 95% CI: 1.12; 2.10, p = 0.0071, I2 = 81.2%). These analyses indicated that vitamin D status was related to the risk of ASD. The detection and appropriate intervention of vitamin D deficiency in ASD patients and pregnant and lactating women have clinical and public significance.
... Although intervention studies will give much yield, observational studies still carry on their shoulders a big task of unveiling vitamin D secrets as randomized controlled trials still have a lot of limitations that limit their validity (17) . Furthermore, serum vitamin D can be influenced by Genetic and epigenetic factors (18) . That further disturbs the homogenization of target population among different studies, thus, biasing their results. ...
... These factors include variation in sun exposure, age, sex, obesity, or chronic illnesses [8]. Moreover, it has been shown that polymorphisms of genes involved in the metabolism, catabolism, transport, or binding of vitamin D to VDR might affect vitamin D concentrations [9]. ...
Vitamin D plays a role not only in the proper functioning of the skeletal system and the calcium-phosphate equilibrium, but also in the immune system, the cardiovascular system and the growth and division of cells. Although numerous studies have reported on the analysis of vitamin D status in various groups of patients, the clinical significance of measurements of vitamin D forms and metabolites remains ambiguous. This article reviews the reports analyzing the status of vitamin D in various chronic states. Particular attention is given to factors affecting measurement of vitamin D forms and metabolites. Relevant papers published during recent years were identified by an extensive PubMed search using appropriate keywords. Measurement of vitamin D status proved to be a useful tool in diagnosis and progression of metabolic syndrome, neurological disorders and cancer. High performance liquid chromatography coupled with tandem mass spectrometry has become the preferred method for analyzing the various forms and metabolites of vitamin D in biological fluids. Factors influencing vitamin D concentration, including socio-demographic and biochemical factors as well as the genetic polymorphism of the vitamin D receptor, along with vitamin D transporters and enzymes participating in vitamin D metabolism should be considered as potential confounders of the interpretation of plasma total 25(OH)D concentrations.
Chronic diseases continue to globally represent the top cause of death. Although their aetiology is diverse, anthropogens (including factors related to modern lifestyles or behaviours) are considered common risk factors for meta-inflammation and activation of the inflammatory-oxidative cascade involved in the development and progression of many chronic diseases. The interaction of individuals’ genetic background and/or epigenetic changes with exposure to anthropogens and chemicals may represent the early stages of the pathogenesis of chronic diseases such as cancer and cardiovascular diseases, etc. Time-depending variations in anthropogens exposure (particularly during critical exposure windows) can play a key role in their pathophysiology. Since all these elements contribute differently across individuals for the development of chronic diseases, personalized medicine should consider all the responsible factors involved in the development and progression of these diseases in order to optimize their management and treatment. In addition, the identification of the main risk factors associated with meta-inflammation can make a real difference for providing appropriate and disease-tailored health services.
The goal of this Research Topic is to identify new mechanisms involved in the pathogenesis of chronic diseases and to highlight how lifestyle, nutritional and environmental interventions (apart from specific pharmacologic treatments), can influence the prognosis of such diseases. New approach methodologies (NAMs) can serve to identify specific new targets for personalized interventions that should be translated into clinical studies for proving their efficacy and safety.
This Research Topic is aimed to identify the newest research in the field of personalized medicine in chronic diseases including, but not limited to, genomic medicine. Here, we will focus primarily on the following themes:
• Role of meta-inflammation and inflammatory-oxidative cascade in certain chronic diseases and possible preventive strategies
• Nutritional status and nutritional interventions for the prevention and management of chronic diseases
• Nutritional intervention (e.g., use of nutraceuticals) as a complement to the standard pharmacological treatments for chronic diseases
We welcome you to contribute to this collection with Mini-reviews, Reviews, Perspectives, Protocols, General Commentaries, and Original Research Articles on the topic.
This study assessed the vitamin D status among women in South-East Oases of Morocco. Two hundred thirty-three healthy volunteer women were recruited at five urban and rural health centers. Hypovitaminosis D is very common in this region and correlated to age, monthly income, skin color, daily sun exposure, BMI, and body fat percentage.PurposeThis study assessed the vitamin D status among women in the Draa-Tafilalet region and its relationship with clinical, anthropometric, and behavioral parameters.Methods
The study was carried out with 233 women in consultation at five urban and rural health centers in the South-East region of Morocco. The data collected relate to age, monthly income, educational level, BMI, body fat percentage, daily sun exposure, physical activity level, veil wear, and skin color. The plasma determination of vitamin D was measured by immunofluorescence. Statistical analyses were performed using Python and Jamovi.ResultsThe median 25(OH)D plasma concentration was 9.95 ng/mL (IQR: 8–13.18). A total of 50.64% of women had 25(OH)D levels below 10 ng/ml and 47.21% had levels between 10 and 30 ng/mL. Statistical tests showed an association between hydroxyvitamin D plasma levels and age (r = − 0.139; p = 0.034), monthly income (p = 0.001), BMI (r = − 0.200; p = 0.002), body fat percentage (r = − 0.131; p = 0.049), daily sun exposure (r = 0.165; p = 0.012), and skin color (p < 0.001). Binomial logistic regression showed that darker skin was associated with vitamin D deficiency (< 10 ng/mL). It also showed that high income and longer sun exposure could be protecting factors against vitamin D deficiency.Conclusion
The plasma concentrations of vitamin D in women in the Draa-Tafilalet region were low compared to expected results for a high sunshine time area.
We discuss, with a biocultural perspective, the connection between living condition related to the Great Peasants’ Revolt and health status of the nonadult population from the 16th century North-eastern Italy, with a particular focus on those caused by micronutrients C and D. We analysed forty-one skeletons of nonadults in primary deposition with macroscopic examination coupled with a literature review aimed at providing a differential diagnosis. Eleven nonadults present probable cases of rickets, twelve show evidence that seems to be related to scurvy, while ten individuals feature a pattern consistent with a co-occurrence condition. Finally, eight subjects have no pathological changes or evidence, and that may be considered strictly related to C or D deficiency.
This study provides a significant example of pathological lesion on nonadults coming from the same area and framed in a limited chronological period. In addition, the sample is distinguished by the number of subjects and the good preservation of their bone tissue. Finally, the work is of primary importance as the Italian panorama lacks exhaustive paleopathological publications.
An association between vitamin D deficiency and hypertension has been observed in numerous studies. However, blood pressure improvements resulting from supplementation with vitamin D have been inconsistent. The causal relationship between vitamin D deficiency and hypertension is still unclear and was investigated in this family-based study. A total of 1370 individuals from both vitamin D deficiency and hypertension families were included. First, the heritability of vitamin D deficiency was estimated by the Falconer method. Second, SNPs (single nucleotide polymorphisms) of vitamin D metabolic and functional pathway genes associated with vitamin D deficiency were screened by a family-based association test, and the findings were further verified in nuclear families with vitamin D deficiency. Finally, a family-based association test was applied to investigate the association between selected SNPs associated with vitamin D deficiency and hypertension. The heritability of vitamin D deficiency was 50.4% in this family-based study. Allele C of rs3847987 was a risk factor for vitamin D deficiency (OR: 1.639, 95% CI: 1.170–2.297, P = 0.004). Furthermore, a family-based association of rs3847987 with hypertension was found in both additive and recessive models (P < 0.05). In addition, vitamin D deficiency was associated with hypertension (OR: 1.317, 95% CI: 1.022–1.698, P = 0.033). In conclusion, rs3847987 in the VDR gene was associated with both vitamin D deficiency and hypertension. Therefore, vitamin D deficiency may be a causal factor for hypertension. Note:rs3847987 is single nucleotide polymorphism of vitamin D metabolic pathway gene VDR. According to the principle of Mendelian Randomization study, if rs3847987 was associated with vitamin D deficiency as well as hypertention, and the association between vitamin D deficiency and hypertention was observed. Then, it could be come to the conclusion that vitamin D deficiency may be a causal factor of hypertention.
Obesity is a globally expanding silent epidemic having multiple risk factors and consequences associated with it. Genetic factors have been found to be playing undeniable roles in obesity. Intermingled relationship between epigenetics, metagenomics, and the environment influences obesity traits. High precision diagnostic tools have outlined many single nucleotide polymorphisms (SNPs), as well as many novel genes, that have been identified that create an obesogenic environment. Rare single-gene diseases can lead to early childhood obesity and less satiety. With almost 30% of the global population being under the grip of obesity, the coming days are alarming. This review summarizes the existing knowledge on the genetic causes of obesity including the epidemiology as well as the issues of concern and new additions to the list. Furthermore, we discuss the ways to enhance the healthcare outcome for patients of obesity through interdepartmental collaborations apart from pharmacological therapy that is still limited to a few drugs. The teamwork of geneticists, genetic counselors, physicians, bariatric surgeons, nurses, endocrinologists, and pharmacists may provide promising results in intervention.
Obesity is a globally expanding silent epidemic having multiple risk factors and consequences associated with it. Genetic factors have been found to be playing undeniable roles in obesity. Intermingled relationship between epigenetics, metagenomics, and the environment influences obesity traits. High precision diagnostic tools have outlined many single nucleotide polymorphisms (SNPs), as well as many novel genes, that have been identified that create an obesogenic environment. Rare single-gene diseases can lead to early childhood obesity and less satiety. With almost 30% of the global population being under the grip of obesity, the coming days are alarming. This review summarizes the existing knowledge on the genetic causes of obesity including the epidemiology as well as the issues of concern and new additions to the list. Furthermore, we discuss the ways to enhance the healthcare outcome for patients of obesity through interdepartmental collaborations apart from pharmacological therapy that is still limited to a few drugs. The teamwork of geneticists, genetic counselors, physicians, bariatric surgeons, nurses, endocrinologists, and pharmacists may provide promising results in intervention.
Importance:
Epstein-Barr virus and its acute manifestation, infectious mononucleosis (IM), are associated with an increased risk of multiple sclerosis (MS). Whether this association is confounded by susceptibility to infection is still debated.
Objective:
To assess whether hospital-diagnosed IM during childhood, adolescence, or young adulthood is associated with subsequent MS diagnosis independent of shared familial factors.
Design, setting, and participants:
This population-based cohort study used the Swedish Total Population Register to identify individuals born in Sweden from January 1, 1958, to December 31, 1994. Participants aged 20 years were followed up from January 1, 1978, to December 31, 2018, with a median follow-up of 15.38 (IQR, 8.68-23.55; range, 0.01-40.96) years. Data were analyzed from October 2020 to July 2021.
Exposure:
Hospital-diagnosed IM before 25 years of age.
Main outcomes and measures:
Diagnoses of MS from 20 years of age were identified. Risk of an MS diagnosis associated with IM in childhood (birth to 10 years of age), adolescence (11-19 years of age), and early adulthood (20-24 years of age [time-dependent variable]) were estimated using conventional and stratified (to address familial environmental or genetic confounding) Cox proportional hazards regression.
Results:
Of the 2 492 980 individuals (1 312 119 men [52.63%] and 1 180 861 women [47.37%]) included, 5867 (0.24%) had an MS diagnosis from 20 years of age (median age, 31.50 [IQR, 26.78-37.54] years). Infectious mononucleosis in childhood (hazard ratio [HR], 1.98; 95% CI, 1.21-3.23) and adolescence (HR, 3.00; 95% CI, 2.48-3.63) was associated with an increased risk of an MS diagnosis that remained significant after controlling for shared familial factors in stratified Cox proportional hazards regression (HRs, 2.87 [95% CI, 1.44-5.74] and 3.19 [95% CI, 2.29-4.46], respectively). Infectious mononucleosis in early adulthood was also associated with risk of a subsequent MS diagnosis (HR, 1.89; 95% CI, 1.18-3.05), but this risk was attenuated and was not significant after controlling for shared familial factors (HR, 1.51; 95% CI, 0.82-2.76).
Conclusions and relevance:
These findings suggest that IM in childhood and particularly adolescence is a risk factor associated with a diagnosis of MS, independent of shared familial factors.
Background:
Clinical demand for nutrigenomics testing (NGT) is increasing, underscoring the importance of assessing healthcare professional (HCP) competence and clinical actions with NGT in practice. While previous studies have explored HCP perceptions of NGT, no study has examined real HCP experiences with NGT in practice.
Objective:
The objective of this study was to evaluate the clinical experience of providing NGT among early adopter HCPs who have used NGT in their practice. We hypothesized that HCP clinical actions after NGT would differ according to HCP personal experience undergoing genetic testing (GT) as well as years in practice.
Design:
An online survey questionnaire was administered to HCPs (n = 70) who have provided NGT in practice. χ2 tests, tests for trend, and logistic regression were used to compare HCP characteristics with post-NGT outcomes.
Results:
HCPs with fewest years in practice (<5 years) comprised the lowest proportion of respondents (16%). Most HCPs reported good understanding of NGT results and 92% made genetic-based dietary recommendations to patients following NGT. HCP personal use of GT increased significantly with increasing years in practice (<5 years: 36%, 5-10 years: 53%, 11-20 years: 70%, and >20 years: 85%, p trend = 0.003). Requesting patient bloodwork because of NGT results increased significantly with HCP years in practice when HCPs with <5 years in practice were not considered (5-10 years: 19%, 11-20 years: 28%, and >20 years: 60%, p trend = 0.010). A near significant difference was observed where a greater proportion of HCPs who had personally undergone GT reported requesting patient bloodwork (personal use: 46% vs. no personal use: 23%, p-χ2 = 0.066).
Conclusion:
Early HCP adopters of NGT utilize the test results to provide genetic-based dietary recommendations to patients. Clinical action after NGT currently appears to be driven by HCP years in practice, but HCP personal use of GT may also be a factor.
Although vitamin D deficiency is known to be a risk factor for some psychological disorders, there have been few studies on the effects of vitamin D supplementation on their symptoms. Depression and aggression are common mental disorders and are associated with disability and disease burden. We aimed to evaluate the effectiveness of high-dose vitamin D supplementation on depression and aggression scores in adolescent girls. Nine hundred forty adolescent girls received vitamin D3 at a dose of 50,000 IU/week for 9 weeks. Anthropometric parameters and blood pressure were measured using standard protocols at the baseline and at the end of the study. Depression score was evaluated using the Beck Depression Inventory–II and aggression was evaluated using the Buss-Perry Aggression Questionnaire at baseline and at the end of the study. Comparison among the four categories of depression score (normal, mild, moderate, and severe) revealed no significant differences in demographic and anthropometric parameters at baseline. After 9 weeks of vitamin D supplementation, there was a significant reduction on mild, moderate, and severe depression score. However, vitamin D supplementation had no significant effect on aggression score. Our results suggest that supplementation with vitamin D may improve depressive symptoms among adolescent girls, as assessed by questionnaire, but not aggression score. Formal, larger, randomized controlled studies are required to confirm this effect on cases with different degrees of depression.
Vitamin D is known for its role in the regulation of gene expression via the vitamin D receptor, a nuclear transcription factor. More recently, a role for vitamin D in regulating DNA methylation has been identified as an additional mechanism of modulation of gene expression. How methylation status influences vitamin D metabolism and response pathways is not yet clear. Therefore, we aimed to assess the relationship between plasma 25-hydroxycholecalciferol (25(OH)D) and the methylation status of vitamin D metabolism enzyme genes (CYP2R1, CYP27B1 and CYP24A1) and the vitamin D receptor gene (VDR). This analysis was conducted in the context of dietary vitamin D, and background methyl donor related biochemistry, with adjustment for several dietary and lifestyle variables. Percentage methylation at CpG sites was assessed in peripheral blood cells using methylation sensitive and dependent enzymes and qPCR. Standard analytical techniques were used to determine plasma 25(OH)D and homocysteine, and serum folate and B12, with the relationship to methylation status assessed using multi-variable regression analysis. CYP2R1 and VDR methylation were found to be independent predictors of plasma 25(OH)D, when adjusted for vitamin D intake and other lifestyle variables. CYP24A1 was related to plasma 25(OH)D directly, but not in the context of vitamin D intake. Methyl-group donor biochemistry was associated with the methylation status of some genes, but did not alter the relationship between methylation and plasma 25(OH)D. Modulation of methylation status of CYP2R1, CYP24A1 and VDR in response to plasma 25(OH)D may be part of feedback loops involved in maintaining vitamin D homeostasis, and may explain a portion of the variance in plasma 25(OH)D levels in response to intake and sun exposure. Methyl-group donor biochemistry, while a potential independent modulator, did not alter this effect.
Fibroblast growth factor 23 (FGF23), a bone-derived hormone, participates in the hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25-dihydroxyvitamin D, plasma phosphate (Pi), and diet. Inappropriately high serum FGF23, seen in certain genetic and acquired disorders, results in urinary phosphate wasting and impaired bone mineralization. This study investigated the impact of FGF23 gene variation on phosphate homeostasis and bone health. The study included 183 children and adolescents (110 girls) aged 7-19 years (median 13.2 years). Urine and blood parameters of calcium and phosphate homeostasis were analyzed. Bone characteristics were quantified by DXA and peripheral quantitative computed tomography (pQCT). Genetic FGF23 variation was assessed by direct sequencing of coding exons and flanking intronic regions. Nine FGF23 polymorphisms were detected; three of them were common: rs3832879 (c.212-37insC), rs7955866 (c.716C > T, p.T239M) and rs11063112 (c.2185A > T). Four different haplotypes and six different diplotypes were observed among these three polymorphisms. The variations in FGF23 significantly associated with plasma PTH and urinary Pi excretion, even after adjusting for relevant covariates. FGF23 variations independently associated with total hip BMD Z-score, but not with other bone outcomes. In instrument analysis, genetic variance in FGF23 was considered a weak instrument as it only induced small variations in circulating FGF23, PTH and Pi concentrations (F statistic less than 10). The observed associations between FGF23 variations and circulating PTH, and Pi excretion and total hip BMD Z-scores suggest that FGF23 polymorphisms may play a role in mineral homeostasis and bone metabolism.
Context:
Adequate serum 25-hydroxyvitamin D concentrations, [25(OH)D], are required for optimal bone health, and low levels are associated with chronic diseases.
Objective:
We investigated whether 41 candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR, and CASR) are associated with [25(OH)D] or modify the increase in [25(OH)D] from vitamin D3 supplementation.
Design and setting:
Baseline and year 1 [25(OH)D] measurements from a randomized controlled trial conducted at 11 clinical centers in the United States.
Participants:
A total of 1787 healthy non-Hispanic white participants aged 45-75 years.
Interventions:
Vitamin D3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo.
Main outcome measures:
Genotype main effects and interactions with vitamin D3 treatment estimated using multiple linear regression.
Results:
The baseline serum [25(OH)D] was 25.4 ± 8.7 ng/mL (mean ± SD). Associations with baseline levels were discovered for SNPs in CYP24A1 (rs2209314, rs2762939) and confirmed for SNPs in GC and CYP2R1. After 1 year, [25(OH)D] increased on average by 6.1 ± 8.9 ng/mL on vitamin D3 treatment and decreased by 1.1 ± 8.4 ng/mL on placebo. The increase in [25(OH)D] due to vitamin D3 supplementation was modified by genotypes at rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR.
Conclusions:
The increase in [25(OH)D] attributable to vitamin D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.
Environmental factors such as diet, intake of vitamin D supplements and exposure to sunlight are known to influence serum vitamin D concentrations. Genetic epidemiology of vitamin D is in its infancy and a better understanding on how genetic variation influences vitamin D concentration is needed. We aimed to analyse previously reported vitamin D-related polymorphisms in relation to serum 25(OH)D concentrations in 201 healthy Danish families with dependent children in late summer in Denmark. Serum 25(OH)D concentrations and a total of 25 SNPs in GC, VDR, CYP2R1, CYP24A1, CYP27B1, C10or88 and DHCR7/NADSYN1 genes were analysed in 758 participants. Genotype distributions were in Hardy-Weinberg equilibrium for the adult population for all the studied polymorphisms. Four SNPs in CYP2R1 (rs1562902, rs7116978, rs10741657 and rs10766197) and six SNPs in GC (rs4588, rs842999, rs2282679, rs12512631, rs16846876 and rs17467825) were statistically significantly associated with serum 25(OH)D concentrations in children, adults and all combined. Several of the SNPs were in strong linkage disequilibrium, and the associations were driven by CYP2R1-rs10741657 and rs10766197, and by GC-rs4588 and rs842999. Genetic risk score analysis showed that carriers with no risk alleles of CYP2R1-rs10741657 and rs10766197, and/or GC rs4588 and rs842999 had significantly higher serum 25(OH)D concentrations compared to carriers of all risk alleles. To conclude, our results provide supporting evidence that common polymorphisms in GC and CYP2R1 are associated with serum 25(OH)D concentrations in the Caucasian population and that certain haplotypes may predispose to lower 25(OH)D concentrations in late summer in Denmark.
Aberrant methylation of CpG islands (CGI) occurs in many genes expressed in colonic epithelial cells, and may contribute to the dysregulation of signalling pathways associated with carcinogenesis. This cross-sectional study assessed the relative importance of age, nutritional exposures and other environmental factors in the development of CGI methylation. Rectal biopsies were obtained from 185 individuals (84 male, 101 female) shown to be free of colorectal disease, and for whom measurements of age, body size, nutritional status and blood cell counts were available. We used quantitative DNA methylation analysis combined with multivariate modelling to investigate the relationships between nutritional, anthropometric and metabolic factors and the CGI methylation of 11 genes, together with LINE-1 as an index of global DNA methylation. Age was a consistent predictor of CGI methylation for 9/11 genes but significant positive associations with folate status and negative associations with vitamin D and selenium status were also identified for several genes. There was evidence for positive associations with blood monocyte levels and anthropometric factors for some genes. In general, CGI methylation was higher in males than in females and differential effects of age and other factors on methylation in males and females were identified. In conclusion, levels of age-related CGI methylation in the healthy human rectal mucosa are influenced by gender, the availability of folate, vitamin D and selenium, and perhaps by factors related to systemic inflammation. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
SummaryThis review describes the vitamin D status in different regions of the world with the objective of understanding the scope
of hypovitaminosis D and the factors related to its prevalence that may contribute to the pathogenesis of osteoporosis and
fragility fractures.
IntroductionVitamin D status has been linked to the pathogenesis of hip fractures as well as other skeletal and non-skeletal disorders.
The purpose of this review is to provide a global perspective of vitamin D status across different regions of the world and
to identify the common and significant determinants of hypovitaminosis D.
MethodsSix regions of the world were reviewed—Asia, Europe, Middle East and Africa, Latin America, North America, and Oceania—through
a survey of published literature.
ResultsThe definition of vitamin D insufficiency and deficiency, as well as assay methodology for 25-hydroxyvitamin D or 25(OH)D,
vary between studies. However, serum 25(OH)D levels below 75nmol/L are prevalent in every region studied whilst levels below
25nmol/L are most common in regions such as South Asia and the Middle East. Older age, female sex, higher latitude, winter
season, darker skin pigmentation, less sunlight exposure, dietary habits, and absence of vitamin D fortification are the main
factors that are significantly associated with lower 25(OH)D levels.
ConclusionReports from across the world indicate that hypovitaminosis D is widespread and is re-emerging as a major health problem globally.
The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.
Plasma concentrations of biologically active vitamin D (1,25-(OH)2D) are tightly controlled via feedback regulation of renal 1α-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)2D levels are significantly elevated, suggesting a role in pregnancy progression. Epigenetic regulation of CYP27B1 and CYP24A1 has previously been described in cell and animal models, and despite emerging evidence for a critical role of epigenetics
in placentation generally, little is known about the regulation of enzymes modulating vitamin D homeostasis at the fetomaternal
interface. In this study, we investigated the methylation status of genes regulating vitamin D bioavailability and activity
in the placenta. No methylation of the VDR (vitamin D receptor) and CYP27B1 genes was found in any placental tissues. In contrast, the CYP24A1 gene is methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue.
No methylation was detected in any somatic human tissue tested. Methylation was also evident in marmoset and mouse placental
tissue. All three genes were hypermethylated in choriocarcinoma cell lines, highlighting the role of vitamin D deregulation
in this cancer. Gene expression analysis confirmed a reduced capacity for CYP24A1 induction with promoter methylation in primary cells and in vitro reporter analysis demonstrated that promoter methylation directly down-regulates basal promoter activity and abolishes vitamin
D-mediated feedback activation. This study strongly suggests that epigenetic decoupling of vitamin D feedback catabolism plays
an important role in maximizing active vitamin D bioavailability at the fetomaternal interface.
Vitamin D is implicated in a wide range of health outcomes, and although environmental predictors of vitamin D levels are known, the genetic drivers of vitamin D status remain to be clarified. African Americans are a group at particularly high risk for vitamin D insufficiency but to date have been virtually absent from studies of genetic predictors of circulating vitamin D levels. Within the Southern Community Cohort Study, we investigated the association between 94 single nucleotide polymorphisms (SNPs) in five vitamin D pathway genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1) and serum 25-hydroxyvitamin D (25(OH)D) levels among 379 African American and 379 Caucasian participants. We found statistically significant associations with three SNPs (rs2298849 and rs2282679 in the GC gene, and rs10877012 in the CYP27B1 gene), although only for African Americans. A genotype score, representing the number of risk alleles across the three SNPs, alone accounted for 4.6% of the variation in serum vitamin D among African Americans. A genotype score of 5 (vs. 1) was also associated with a 7.1 ng/mL reduction in serum 25(OH)D levels and a six-fold risk of vitamin D insufficiency (<20 ng/mL) (odds ratio 6.0, p = 0.01) among African Americans. With African ancestry determined from a panel of 276 ancestry informative SNPs, we found that high risk genotypes did not cluster among those with higher African ancestry. This study is one of the first to investigate common genetic variation in relation to vitamin D levels in African Americans, and the first to evaluate how vitamin D-associated genotypes vary in relation to African ancestry. These results suggest that further evaluation of genetic contributors to vitamin D status among African Americans may help provide insights regarding racial health disparities or enable the identification of subgroups especially in need of vitamin D-related interventions.
Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations.
Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n = 1,439) were analyzed using a single-nucleotide polymorphism (SNP) tagging approach, with a subset (n = 404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods.
Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia; however, a significant gene-level association between GC and 25(OH)D concentrations (P < 0.01) was observed. At the individual SNP level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, and rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted P < 0.01) and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted P = 0.01).
These results show a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations. Impact: Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia.
Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.
We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.
Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10(-4)), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10(-3)) and CYP2R1 (P = 3.0 × 10(-3)).
Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.
Serum 25-hydroxyvitamin D [25(OH)D] concentrations can be affected by several environmental and individual factors. It is not clear to what extent genetic influences play a role in determining vitamin D status. Thus far, studies on the heritability of vitamin D have provided conflicting results.
We estimated the heritability of vitamin D concentrations and the effect of season on heritability estimates.
We measured serum 25(OH)D concentrations in 510 middle-aged, male twins (310 monozygotic and 200 dizygotic twins) selected from the Vietnam Era Twin Registry. Generalized estimating equations were used to test the association between 25(OH)D and other study factors. Structural equation modeling was used to estimate the heritability of 25(OH)D.
The twins' mean (±SD) age was 55 ± 2.8 y. The mean (±SD) 25(OH)D concentration was 38.4 ± 23.3 ng/mL with a substantial seasonal variation (a 6.1-ng/mL lower value during the winter than during the summer, P = 0.003). Approximately 70% of the variation in 25(OH)D concentrations during the winter was explained by genetic factors. However, in the summer, 25(OH)D concentrations were not heritable. During the summer, 53% of the variation in 25(OH)D concentrations was due to shared environmental factors, and 47% of the variation in 25(OH)D concentrations was due to unique environmental factors.
Serum 25(OH)D concentrations are highly heritable during the winter season only. In the summer, environmental conditions (eg, sun exposure) prevail over genetic backgrounds in determining serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00017836.
The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including
rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European
ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific
component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10−30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10−22) and rs1155563 (P = 3.8 × 10−25). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin
D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10−7], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the
region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10−7); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P = 1.4 × 10−5). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations
with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10−49), NADSYN1/DHCR7 (P = 3.4 × 10−9) and CYP2R1 (P = 2.9 × 10−17), but not C10orf88 (P = 2.4 × 10−5).
Vitamin D deficiency has been associated with many chronic illnesses, but little is known about its relationship with chronic obstructive pulmonary disease (COPD).
Serum 25-hydroxyvitamin D (25-OHD) levels were measured in 414 (ex)-smokers older than 50 years and the link between vitamin D status and presence of COPD was assessed. The rs7041 and rs4588 variants in the vitamin D-binding gene (GC) were genotyped and their effects on 25-OHD levels were tested.
In patients with COPD, 25-OHD levels correlated significantly with forced expiratory volume in 1 s (FEV(1)) (r=0.28, p<0.0001). Compared with 31% of the smokers with normal lung function, as many as 60% and 77% of patients with GOLD (Global Initiative for Obstructive Lung Disease) stage 3 and 4 exhibited deficient 25-OHD levels <20 ng/ml (p<0.0001). Additionally, 25-OHD levels were reduced by 25% in homozygous carriers of the rs7041 at-risk T allele (p<0.0001). This correlation was found to be independent of COPD severity, smoking history, age, gender, body mass index, corticosteroid intake, seasonal variation and rs4588 (p<0.0001). Notably, 76% and 100% of patients with GOLD stage 3 and 4 homozygous for the rs7041 T allele exhibited 25-OHD levels <20 ng/ml. Logistic regression corrected for age, gender and smoking history further revealed that homozygous carriers of the rs7041 T allele exhibited an increased risk for COPD (OR 2.11; 95% CI 1.20 to 3.71; p=0.009).
Vitamin D deficiency occurs frequently in COPD and correlates with severity of COPD. The data warrant vitamin D supplementation in patients with severe COPD, especially in those carrying at-risk rs7041 variants.
Although environmental factors, mainly nutrition and UV-B radiation, have been considered major determinants of vitamin D status, they have only explained a modest proportion of the variation in serum 25-hydroxyvitamin D. We aimed to study the seasonal impact of genetic factors on serum 25-hydroxyvitamin D concentrations.
204 same-sex twins, aged 39-85 years and living at northern latitude 60 degrees, were recruited from the Swedish Twin Registry. Serum 25-hydroxyvitamin D was analysed by high-pressure liquid chromatography and mass spectrometry. Genetic modelling techniques estimated the relative contributions of genetic, shared and individual-specific environmental factors to the variation in serum vitamin D. The average serum 25-hydroxyvitamin D concentration was 84.8 nmol/l (95% CI 81.0-88.6) but the seasonal variation was substantial, with 24.2 nmol/l (95% CI 16.3-32.2) lower values during the winter as compared to the summer season. Half of the variability in 25-hydroxyvitamin D during the summer season was attributed to genetic factors. In contrast, the winter season variation was largely attributable to shared environmental influences (72%; 95% CI 48-86%), i.e., solar altitude. Individual-specific environmental influences were found to explain one fourth of the variation in serum 25-hydroxyvitamin D independent of season.
There exists a moderate genetic impact on serum vitamin D status during the summer season, probably through the skin synthesis of vitamin D. Further studies are warranted to identify the genes impacting on vitamin D status.
Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake.
Background:
The prevalence of Vitamin D deficiency is increasing worldwide, which has be shown to be associated with increased risk of cardiovascular disease (CVD), autoimmune disease and metabolic syndrome. These conditions are also associated with a heightened state of inflammation. The aim of the current study was to evaluate the effect of vitamin D supplementation on serum C - reactive protein (CRP) level and Neutrophil-to-lymphocyte ratio (NLR) distribution in a large cohort of adolescent girls.
Methods:
580 adolescent girls were recruited follow by evaluation of CRP and hematological parameters before and after supplementation with vitamin D supplements as 9 of 50000 IU cholecalciferol capsules for 3 months taken at weekly intervals.
Results:
At baseline, serum hs-CRP level was 0.9 (95%CI: 0.5-1.8), while this value after intervention was reduced to 0.8 (95%CI: 0.3-1.6; P = 0.007). Similar results were also detected for NLR (e.g., NLP level was 1.66 ± 0.72 and 1.53 ± 0.67, P = 0.002, before and after therapy with compliance rate of >95.2%). Moreover we found an association between hs-CRP and BMI, triglyceride, white blood cell count and lymphocytes. Interestingly we observed a significant reduction in neutrophil count and CRP level after high dose vitamin D supplementation.
Conclusion:
Our findings showed that the high-dose supplementation of vitamin D affects measures of systemic inflammation: reductions in High-Sensitivity C-Reactive Protein level and Neutrophil-to-lymphocyte ratio (NLR) distribution. This article is protected by copyright. All rights reserved.
The 25-hydroxy vitamin D (25(OH)D) production caused by UVB exposure is usually underestimated as the concurrent degradation of 25(OH)D is not considered. Therefore, the decrease in 25(OH)D was investigated during a 7-week period in winter when ambient UVB is negligible. Twenty-two healthy Danish individuals (113 samples) participated and had a mean and steady maximal 25(OH)D start level of 132 nmol l-1 (range of 68 - 216 nmol l-1) due to long-term UVB treatment prior to this study. In this group with high 25(OH)D start levels, the decrease in 25(OH)D was best described by an exponential model. This suggests a quantitatively larger elimination of 25(OH)D at high 25(OH)D start levels. A linear model (logarithm of 25(OH)D) including personal start levels as intercepts and slope influenced by gender and the vitamin D receptor gene polymorphism rs2228570 explained 87.8% of the observed variation. The mean half-life was 89 days with a difference in half-life of 120 days between a male with rs2228570 genotype GG (59 days) and a female with rs2228570 genotype AA/AG (179 days). Thus, these two parameters explained a large part of the observed inter-individual variation of 25(OH)D. Furthermore, the decrease was analysed in two groups with medium and low 25(OH)D start levels resulting in longer half-lives of 149 days and 199 days, respectively. The longer half-lives at lower 25(OH)D levels may be caused by storage mobilisation, changed catabolism or increased intestinal absorption.
Vitamin D is implicated in several aspects of human physiology, and polymorphisms in the vitamin D receptor gene (VDR) are associated with a variety of neuropsychiatric disorders. The aims of this study are to determine whether VDR polymorphisms are associated with autism spectrum disorder (ASD), to examine serum 25-hydroxyvitamin D (25(OH)D) levels in ASD, and to explore whether VDR polymorphisms influence serum 25(OH)D levels. We investigated 480 subjects (237 children with ASD and 243 healthy controls) for the following VDR polymorphisms: TaqI, BsmI, FokI, ApaI, and Cdx2.Within the same samples, 25(OH)D levels were available only for 85 patients and 82 controls. The Cdx-2 variation was shown to deviate from Hardy–Weinberg equilibrium in the controls and was therefore excluded from the study. We found that the frequency of rare FokI TT, TaqI CC, and BsmI AA genotypes differed significantly between children with ASD and the controls (p = 0.042, p = 0.016, p = 0.038, respectively). After correction for multiple testing, only the TaqI CC genotype remained significant. Further analysis using a recessive model showed that rare genotypes of these polymorphisms were significantly higher in patients compared to controls (p = 0.045, p = 0.005 and p = 0.031, respectively). However, no significant association was found between ApaI and ASD. We found serum 25(OH)D levels to be significantly higher in children with ASD (p < 0.001) and that the FokI polymorphism had an effect on serum 25(OH)D levels in children with ASD (p = 0.041). Additionally, we found the haplotype GTTT (BsmI/TaqI/FokI/ApaI) conferred an increased risk for developing ASD (p = 0.022; odds ratio [95% confidence interval]=2.322 [1.105–4.879]). This is the first clinical study evaluating the association between serum 25(OH)D levels and VDR polymorphisms in children with ASD. Our results demonstrated a significant association between TaqI, BsmI, and FokI polymorphisms and ASD and showed for the first time that FokI polymorphisms and haplotype GTTT (BsmI/TaqI/FokI/ApaI) are associated with an increased risk of ASD. Our findings support the hypothesis that 25(OH)D is involved in the pathophysiology of autism and that serum 25(OH)D levels may be affected by FokI polymorphisms in children with ASD. Our results should be considered as preliminary and needs confirmation by future studies.