scholarly journals The CYP2R1 Enzyme: Structure, Function, Enzymatic Properties and Genetic Polymorphism

2021 ◽  
Vol 24 ◽  
pp. 94-112
Author(s):  
Amelia Nathania Dong ◽  
Boon Hooi Tan ◽  
Yan Pan ◽  
Chin Eng Ong
Keyword(s):  
Vitamin D ◽  
Genetic Polymorphism ◽  
Complex Traits ◽  
Causal Link ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Metabolism ◽  
Catalytic Function ◽  
Access Channel ◽  
Exonic Snps ◽  
Functional Consequences

Since the discovery of its role in vitamin D metabolism, significant progress has been made in the understanding of gene organisation, protein structure, catalytic function, and genetic polymorphism of cytochrome P450 2R1 (CYP2R1). Located on chromosome 11p15.2, CYP2R1 possesses five exons, unlike most other CYP isoforms that carry nine exons. CYP2R1 crystal structure displays a fold pattern typical of a CYP protein, with 12 a-helices as its structural core, and b-sheets mostly arranged on one side, and the heme buried in the interior part of the protein. Overall, CYP2R1 structure adopts a closed conformation with the B′ helix serving as a gate covering the substrate access channel, with the substrate vitamin D3 occupying a position with the side chain pointing toward the heme group. In liver, CYP2R1 25-hydroxylates vitamin D and serves as an important determinant of 25(OH)D level in the tissue and in circulation. While substrate profile has been well studied, inhibitor specificity for CYP2R1 requires further investigation. Both exonic and non-exonic single nucleotide polymorphisms (SNPs) have been reported in CYP2R1, including the CYP2R1*2 carrying Leu99Pro exchange, and a number of non-exonic SNPs with variable functional consequences in gene regulation. A non-exonic SNP, rs10741657, has its causal relationship with diseases established, including that of rickets, ovarian cancer, and multiple sclerosis. The role of other CYP2R1 SNPs in vitamin D deficiency and their causal link to other traits however remain uncertain currently and more studies are warranted to help identify possible physiological mechanisms underlying those complex traits.

scholarly journals Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis

2009 ◽  
Vol 16 (2) ◽  
pp. 133-138 ◽  
Author(s):  
K. Claire Simon ◽  
Kassandra L Munger ◽  
Xing Yang ◽  
Alberto Ascherio
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Conditional Logistic Regression ◽  
Dietary Vitamin ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Metabolism ◽  
Logistic Regression Models ◽  
Gene Environment ◽  
Vitamin D Levels

The extent to which potential genetic determinants of vitamin D levels may be related to multiple sclerosis (MS) risk has not been thoroughly explored. The objective of this study was to determine whether polymorphisms in VDR, CYP27B1, CYP24A1, CYP2R1 and DBP are associated with the risk of MS and whether these variants may modify associations between environmental or dietary vitamin D on MS risk. A nested case-control study was conducted in two, large cohorts of US nurses, including 214 MS cases and 428 age-matched controls. Conditional logistic regression models were used to calculate relative risks (RR) and 95% confidence intervals (CIs) and to assess the significance of gene—environment interactions. No associations were observed for any of the single-nucleotide polymorphisms (SNPs) in VDR, CYP27B1, CYP24A1, CYP2R1 or DBP (p > 0.05 for all). The authors did observe an interaction (p = 0.04) between dietary intake of vitamin D and the vitamin D receptor FokI polymorphism on MS risk. The protective effect of increasing vitamin D was evident only in individuals with the ‘ff ’ genotype (RR = 0.2, 95% CI: 0.06, 0.78; p = 0.02 for 400 IU/day increase). It was concluded that this does not support a role for the selected SNPs involved in vitamin D metabolism in the etiology of MS. The finding of a marginally significant gene—environment interaction requires replication in larger datasets, but suggests future genetic studies may benefit from considering relevant environmental context.

Contribution of CYP27B1 and CYP24A1 genetic variations to the incidence of acute coronary syndrome and to vitamin D serum level

2019 ◽  
Vol 97 (12) ◽  
pp. 1152-1158 ◽  
Author(s):  
Marina Sherif Fam ◽  
Sally I. Hassanein ◽  
Mohamed Farouk Abdel Rahman ◽  
Reem Amr Assal ◽  
Rasha Sayed Hanafi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Acute Coronary Syndrome ◽  
Ultra Performance Liquid Chromatography ◽  
Genetic Variations ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Metabolism ◽  
Public Health Burden ◽  
Hydroxyvitamin D ◽  
Coronary Syndrome ◽  
Vitamin D Levels

Cardiovascular diseases remain a major public health burden worldwide. It was reported that vitamin D protects the cardiovascular system through several mechanisms mainly by hindering atherosclerosis development. Genetic variations in vitamin D metabolic pathway were found to affect vitamin D levels. This study aimed at investigating the association between single nucleotide polymorphisms in genes involved in vitamin D metabolism, CYP27B and CYP24A1; 25-hydroxyvitamin D (25(OH)D) levels; and susceptibility to acute coronary syndrome (ACS). One hundred and eighty-five patients and 138 healthy controls were recruited. CYP24A1 rs2762939 was genotyped using fast real-time PCR, while CYP24A1 rs4809960 and CYP27B1 rs703842 were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism (PCR–RFLP). 25(OH)D3 and 25(OH)D2 levels were measured using ultra-performance liquid chromatography tandem mass spectrum. Vitamin D level was significantly lower in patients than controls (p < 0.05). The GG genotype of rs2762939 was significantly associated with the risk of ACS development, but not correlated to the vitamin D level. rs4809960 and rs703842 genetic variations were not associated with ACS nor with 25(OH)D level. The genetic variant rs2762939 of CYP24A1 is remarkably associated with ACS. Meanwhile, the variants rs4809960 and rs703842 are not associated with ACS incidence.

scholarly journals Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1954 ◽  
Author(s):  
Veronika Fedirko ◽  
Hannah Mandle ◽  
Wanzhe Zhu ◽  
David Hughes ◽  
Afshan Siddiq ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vitamin D ◽  
Multiple Testing ◽  
A Priori ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Vitamin D Metabolism ◽  
Gene Pathway ◽  
Vitamin D Levels ◽  
Large Populations

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini–Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

scholarly journals Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D–Related Genetic Variants

2017 ◽  
Vol 102 (8) ◽  
pp. 2941-2949 ◽  
Author(s):  
Rebecca J Moon ◽  
Nicholas C Harvey ◽  
Cyrus Cooper ◽  
Stefania D’Angelo ◽  
Elizabeth M Curtis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Group Analysis ◽  
Additive Model ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Metabolism ◽  
Single Nucleotide ◽  
White Ethnicity ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Cholecalciferol Supplementation

Abstract Context Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation. Design Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation. Setting Hospital antenatal clinics. Participants In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped. Interventions 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery. Main Outcome Measure 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]. Results Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P &lt; 0.004]. In contrast, rs10741657 (CYP2R1) (β = −5.2 nmol/L; 95% CI, −8.2 to −2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not. Conclusions Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity.

scholarly journals Vitamin D and Rehabilitation after Stroke: Status of Art

2020 ◽  
Vol 10 (6) ◽  
pp. 1973 ◽  
Author(s):  
Mariacristina Siotto ◽  
Massimo Santoro ◽  
Irene Aprile
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Stroke Recovery ◽  
Stroke Severity ◽  
Nucleotide Polymorphisms ◽  
Stroke Patients ◽  
Vitamin D Metabolism ◽  
Rehabilitation Treatment ◽  
Post Stroke ◽  
Vitamin D Levels

Stroke is the first cause of disability in the population and post-stroke patients admitted to rehabilitation units often present a malnutrition status which can influence nutritional indices and then vitamin levels. Vitamin D deficiency seems implicated beyond stroke severity and stroke risk, and also affects post-stroke recovery. Some studies on vitamin D levels and outcome in stroke patients are available but very few data on vitamin D levels and outcome after rehabilitation treatment are reported. This literature review shows the possible relationship between vitamin D deficiency and recovery in post-stroke patients undergoing rehabilitation treatment. Moreover, because several studies have reported that single nucleotide polymorphisms and promoter methylation in genes are involved in vitamin D metabolism and might affect circulating vitamin D levels, these aspects are evaluated in the current paper. From the studies evaluated in this review, it emerges that vitamin D deficiency could not only have an important role in the recovery of patients undergoing rehabilitation after a stroke, but that genetic and epigenetic factors related to vitamin D levels could have a crucial role on the rehabilitation outcome of patients after stroke. Therefore, further studies are necessary on stroke patients undergoing rehabilitation treatment, including: (a) the measurement of the 25(OH) vitamin D serum concentrations at admission and post rehabilitation treatment; (b) the identification of the presence/absence of CYP2R1, CYP27B1, CYP24A1 and VDR polymorphisms, and (c) analysis of the methylation levels of these genes pre- and post-rehabilitation treatment.

scholarly journals Associations between Genetic Variants in the Vitamin D Metabolism Pathway and Severity of COVID-19 among UAE Residents

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3680
Author(s):  
Fatme Al-Anouti ◽  
Mira Mousa ◽  
Spyridon N. Karras ◽  
William B. Grant ◽  
Zainab Alhalwachi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
United Arab Emirates ◽  
Genetic Variants ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Potential Risk Factors ◽  
25 Hydroxyvitamin D

Vitamin D has many effects on cells in the immune system. Many studies have linked low vitamin D status with severity of COVID-19. Genetic variants involved in vitamin D metabolism have been implicated as potential risk factors for severe COVID-19 outcomes. This study investigated how genetic variations in humans affected the clinical presentation of COVID-19. In total, 646 patients with SARS-CoV-2 infection were divided into two groups: noncritical COVID-19 (n = 453; 70.12%) and a critical group (n = 193; 29.87%). Genotype data on the GC, NADSYN1, VDR, and CYP2R1 genes along with data on serum 25-hydroxyvitamin D levels were compiled in patients admitted to a major hospital in the United Arab Emirates between April 2020 and January 2021. We identified 12 single-nucleotide polymorphisms associated with the critical COVID-19 condition: rs59241277, rs113574864, rs182901986, rs60349934, and rs113876500; rs4944076, rs4944997, rs4944998, rs4944979, and rs10898210; and rs11574018 and rs11574024. We report significant associations between genetic determinants of vitamin D metabolism and COVID-19 severity in the UAE population. Further research needed to clarify the mechanism of action against viral infection in vitamin D deficiency. These variants could be used with vaccination to manage the spread of SARS-CoV-2 and could be particularly valuable in populations in which vitamin D deficiency is common.

scholarly journals Vitamin D Metabolic Pathway Genes Polymorphisms and Their Methylation Levels in Association With Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Tian-Ping Zhang ◽  
Hong-Miao Li ◽  
Qian Huang ◽  
Li Wang ◽  
Xiao-Mei Li
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Metabolic Pathway ◽  
Dominant Mode ◽  
Nucleotide Polymorphisms ◽  
Promoter Regions ◽  
Illumina Hiseq ◽  
Vitamin D Metabolism ◽  
Single Nucleotide ◽  
Illumina Hiseq Platform

Abnormal vitamin D metabolism is involved in the pathogenesis of rheumatoid arthritis (RA). In this study, we evaluated the association of single nucleotide polymorphisms (SNPs) and methylation levels in vitamin D metabolic pathway genes with RA susceptibility. Ten SNPs in vitamin D metabolic pathway genes (CYP2R1, CYP24A1, VDR, CYP27B1) were genotyped in 477 RA patients and 496 controls by improved multiple ligase detection reaction (iMLDR). The methylation levels of the promoter regions of these genes were detected in 122 RA patients and 123 controls using Illumina Hiseq platform. We found that the CYP2R1 rs1993116 GA genotype, CYP27B1 rs4646536 GA genotype, rs4646536 A allele frequencies were significantly increased in RA patients when compared to controls. The decreased risk of rs1993116, rs4646536 was found under the dominant mode in RA patients. However, no significant association was found between CYP2R1 rs7936142, rs12794714, CYP24A1 rs2762934, rs6068816, rs2296239, rs2296241, VDR rs11574129, rs3847987 polymorphism, and RA susceptibility. The VDR, CYP27B1 methylation levels in RA patients were significantly lower than those in controls, while CYP2R1, CYP24A1 methylation levels were not associated with RA. There were no statistical associations between CYP2R1, CYP24A1, VDR, CYP27B1 methylation levels and their respective genotype in RA patients. In addition, plasma 25OHD level in RA patients was significantly lower than that in healthy controls. In summary, our results showed that CYP2R1, CYP27B1 genetic variations were associated with the genetic background of RA, while altered VDR, CYP27B1 methylation levels were related to the risk of RA.

scholarly journals Vitamin D status and pathway genes in five European autoimmune Addison’s disease cohorts

2021 ◽  
Vol 184 (3) ◽  
pp. 377-385
Author(s):  
Marissa Penna-Martinez ◽  
Gesine Meyer ◽  
Anette Boe Wolff ◽  
Beate Skinningsrud ◽  
Corrado Betterle ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Addison’S Disease ◽  
Cross Sectional Study ◽  
Primary Objective ◽  
Addison's Disease ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Status ◽  
Vitamin D Metabolism ◽  
Cross Sectional

Objective While vitamin D regulates immune cells, little is known about it in autoimmune Addison’s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. Design Cross-sectional study. Methods A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). Results Vitamin D deficiency (25(OH)D3 10–20 ng/mL) was highly prevalent in AAD patients (34–57%), 5–22% were severely deficient (<10 ng/mL), 28–38% insufficient (20–30 ng/mL) and only 7–14% sufficient (>30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1 × 10-5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. Conclusion Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

scholarly journals Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies

2020 ◽  
Vol 21 (24) ◽  
pp. 9626
Author(s):  
Adolfo I. Ruiz-Ballesteros ◽  
Mónica R. Meza-Meza ◽  
Barbara Vizmanos-Lamotte ◽  
Isela Parra-Rojas ◽  
Ulises de la Cruz-Mosso
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Serum Levels ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Metabolism ◽  
Single Nucleotide ◽  
High Prevalence

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

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