Influence of Vitamin D Status and Vitamin D3 Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial
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{"title"=>"Influence of Vitamin D Status and Vitamin D3 Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial", "type"=>"journal", "authors"=>[{"first_name"=>"Arash", "last_name"=>"Hossein-nezhad", "scopus_author_id"=>"8307200300"}, {"first_name"=>"Avrum", "last_name"=>"Spira", "scopus_author_id"=>"56831999300"}, {"first_name"=>"Michael F.", "last_name"=>"Holick", "scopus_author_id"=>"56827193200"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84875179200", "sgr"=>"84875179200", "pui"=>"368562489", "pmid"=>"23527013", "doi"=>"10.1371/journal.pone.0058725"}, "id"=>"0b21220a-e186-3692-8803-5c17d9d6c297", "abstract"=>"BACKGROUND: Although there have been numerous observations of vitamin D deficiency and its links to chronic diseases, no studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. The objective of this study was to determine the effect of vitamin D status and subsequent vitamin D supplementation on broad gene expression in healthy adults. (Trial registration: ClinicalTrials.gov NCT01696409).\\n\\nMETHODS AND FINDINGS: A randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D3 daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults in the winter. Microarrays of the 16 buffy coats from eight subjects passed the quality control filters and normalized with the RMA method. Vitamin D3 supplementation that improved serum 25-hydroxyvitamin D concentrations was associated with at least a 1.5 fold alteration in the expression of 291 genes. There was a significant difference in the expression of 66 genes between subjects at baseline with vitamin D deficiency (25(OH)D<20 ng/ml) and subjects with a 25(OH)D>20 ng/ml. After vitamin D3 supplementation gene expression of these 66 genes was similar for both groups. Seventeen vitamin D-regulated genes with new candidate vitamin D response elements including TRIM27, CD83, COPB2, YRNA and CETN3 which have been shown to be important for transcriptional regulation, immune function, response to stress and DNA repair were identified.\\n\\nCONCLUSION/SIGNIFICANCE: Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D.\\n\\nTRIAL REGISTRATION: ClinicalTrials.gov NCT01696409.", "link"=>"http://www.mendeley.com/research/influence-vitamin-d-status-vitamin-d3-supplementation-genome-wide-expression-white-blood-cells-rando-4", "reader_count"=>146, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Student > Doctoral Student"=>8, "Researcher"=>25, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>11, "Other"=>15, "Student > Master"=>30, "Student > Bachelor"=>20, "Lecturer"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Student > Doctoral Student"=>8, "Researcher"=>25, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>11, "Other"=>15, "Student > Master"=>30, "Student > Bachelor"=>20, "Lecturer"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Agricultural and Biological Sciences"=>46, "Business, Management and Accounting"=>1, "Chemistry"=>3, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>11, "Nursing and Health Professions"=>7, "Materials Science"=>1, "Medicine and Dentistry"=>57, "Design"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Sports and Recreations"=>1, "Psychology"=>1, "Social Sciences"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>57}, "Social Sciences"=>{"Social Sciences"=>4}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>1}, "Unspecified"=>{"Unspecified"=>8}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}, "Design"=>{"Design"=>1}, "Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>46}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}}, "reader_count_by_country"=>{"New Zealand"=>1, "United States"=>1, "United Kingdom"=>3, "Australia"=>1, "Germany"=>1}, "group_count"=>8}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/993146"], "description"=>"<p>(A) The candidate sequences of VDREs (B), motifs created based on known VDRE sequences previously reported and (C) motifs based on the sum of these sequences and (D) the location of candidate VDREs of pseudouridylate synthase 3 (PUS3) and the location of other transcription regulation sites in this gene including TATA box, SF1and CCAAT. The major structure of candidate VDREs are based on the consensus sequence RGKTSA (R  =  A or G, K  =  G or T, and S  =  C or G).</p>", "links"=>[], "tags"=>["vdres", "compared"], "article_id"=>656667, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g006", "stats"=>{"downloads"=>1, "page_views"=>47, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sequence_of_candidate_VDREs_compared_with_known_VDREs_/656667", "title"=>"Sequence of candidate VDREs compared with known VDREs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:37:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/993140"], "description"=>"<p>Before supplementation (light green) four subjects were vitamin D deficient with 25(OH)D of 16.2±4.2 ng/ml (dark purple) and the other four subjects were insufficient or sufficient with a 25(OH)D of 27.5±8.4 ng/ml(light purple). After supplementation (dark green) serum levels of 25(OH)D in vitamin D insufficient/sufficient subjects increased to 35.2±8.2 ng/ml (light purple) and in the vitamin deficient subjects increased to 25.1± 4.7 ng/ml(dark purple). Two groups of gene-expression changes are seen based on stimulation (brown) or inhibition (blue) of gene expression post vitamin D<sub>3</sub> supplementation. (Colors ranged from blue to brown; High expression  =  brown, average expression  =  white, low expression  =  blue). Clustering of the 291 genes affected by vitamin D<sub>3</sub> supplementation was based on stimulation (brown) or inhibition (blue) of gene expression. The list of the 291 genes is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058725#pone.0058725.s002\" target=\"_blank\">Table S1</a>.</p>", "links"=>[], "tags"=>["responsive", "genes", "months"], "article_id"=>656661, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heatmaps_of_vitamin_D_responsive_genes_whose_expression_levels_change_after_2_months_vitamin_D_3_supplementation_/656661", "title"=>"Heatmaps of vitamin D responsive genes whose expression levels change after 2 months vitamin D<sub>3</sub> supplementation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:36:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1007763"], "description"=>"<p>The positions and sequences of nucleotide motifs from 5′ upstream to the transcriptional start site for 17 genes identified as being most affected by vitamin D<sub>3</sub> supplementation. The similarity of the candidate VDREs with known VDREs is shown.</p>", "links"=>[], "tags"=>["motif", "sequences", "17", "genes", "supplementation", "vdre"], "article_id"=>668387, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.t002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_motif_sequences_of_17_genes_that_were_most_response_to_vitamin_D_3_supplementation_that_is_identical_or_similar_to_other_known_VDRE_sequences_/668387", "title"=>"The motif sequences of 17 genes that were most response to vitamin D<sub>3</sub> supplementation that is identical or similar to other known VDRE sequences.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-20 02:19:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/993139"], "description"=>"<p>There is no grouping of samples along the first or second principal components (representing 18.6% and 17.9% of the variance in gene expression, respectively) based on the expression of these genes. Sample types of each group before or after vitamin D<sub>3</sub> supplementation are color-coded for the dose of vitamin D<sub>3</sub> supplementation. Red =  2000 IUs and blue =  400 IUs (PoV  =  Possibility of Variance.)</p>", "links"=>[], "tags"=>["16", "microarray"], "article_id"=>656660, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Principal_Component_Analysis_across_16_microarray_samples_/656660", "title"=>"Principal Component Analysis across 16 microarray samples.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:35:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/993136"], "description"=>"<p>Flow Diagram of Study Subjects.</p>", "links"=>[], "tags"=>["diagram"], "article_id"=>656657, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Flow_Diagram_of_Study_Subjects_/656657", "title"=>"Flow Diagram of Study Subjects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:35:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/993148"], "description"=>"<p>After receiving vitamin D<sub>3</sub> supplementation we identified 291 genes whose expression was significantly decreased or increased. Some of these genes influence several pathways that are involved in response to stress and DNA repair, DNA replication, immune regulation, epigenetic modification, transcriptional regulation and other biological functions. In addition vitamin D<sub>3</sub> supplementation influenced the expression of Y RNA and CETN3 that are involved in DNA repair in response to UVR exposure.</p>", "links"=>[], "tags"=>["functions", "genes", "altered", "months"], "article_id"=>656669, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biological_functions_for_genes_whose_expression_levels_were_altered_after_2_months_of_vitamin_D_3_supplementation_/656669", "title"=>"Biological functions for genes whose expression levels were altered after 2 months of vitamin D<sub>3</sub> supplementation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:37:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1007779"], "description"=>"<p>Demographic information including sex, average age and 25(OH)D levels are included (mean ± standard deviation).</p>", "links"=>[], "tags"=>["demographics", "400", "2000", "supplementation"], "article_id"=>668405, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.t001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Subject_demographics_and_total_25_OH_D_levels_before_and_after_400_IU_d_or_2000_IU_d_of_vitamin_D_3_supplementation_for_8_weeks_/668405", "title"=>"Subject demographics and total 25(OH)D levels before and after 400 IU/d or 2000 IU/d of vitamin D<sub>3</sub> supplementation for 8 weeks.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-20 02:20:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/993144"], "description"=>"<p>Before supplementation (light green) four subjects were vitamin D deficient with 25(OH)D of 16.2±4.2 ng/ml (dark purple) and the other four subjects were insufficient or sufficient with a 25(OH)D of 27.5±8.4 ng/ml(light purple). After supplementation (dark green) serum levels of 25(OH)D in vitamin D insufficient/sufficient subjects increased to 35.2±8.2 ng/ml (light purple) and in the vitamin deficient subjects increased to 25(OH)D of 25.1±4.7 ng/ml(dark purple). Two groups of gene-expression changes are seen based on stimulation (brown) or inhibition (blue) of gene expression post vitamin D<sub>3</sub> supplementation. (Colors ranged from blue to brown; High expression  =  brown, average expression  =  white, low expression  =  blue).Expression of 66 genes before supplementation was significantly different in the vitamin D deficient group (dark purple) compared to the vitamin D insufficient/sufficient group (light purple). Clustering of the 66 genes affected by vitamin D status and vitamin D<sub>3</sub> supplementation was based on stimulation (brown) or inhibition (blue) of gene expression.</p>", "links"=>[], "tags"=>["responsive", "genes", "affected"], "article_id"=>656665, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g005", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heatmaps_of_vitamin_D_responsive_genes_affected_by_vitamin_D_status_/656665", "title"=>"Heatmaps of vitamin D responsive genes affected by vitamin D status.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:36:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/993142"], "description"=>"<p>For verification of gene expression real-time PCR was performed for four genes including CD83, TNFAIP3, KLF10 and SBDS. Relationship between two sets of data from microarray and real-time PCR is shown by linear regression with 95% mean prediction interval. The results showed the relative expression of these genes was consistent with the expression observed from the broad gene expression by microarray.</p>", "links"=>[], "tags"=>["microarray", "Real-time"], "article_id"=>656663, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Verification_of_microarray_gene_expression_by_Real_time_PCR_/656663", "title"=>"Verification of microarray gene expression by Real-time PCR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-21 04:36:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1007745"], "description"=>"<p>List of biological functions of the 291 genes whose expression was influenced by vitamin D<sub>3</sub> supplementation.</p>", "links"=>[], "tags"=>["functions", "291", "genes", "influenced"], "article_id"=>668370, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058725.t003", "stats"=>{"downloads"=>4, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_List_of_biological_functions_of_the_291_genes_whose_expression_was_influenced_by_vitamin_D_3_supplementation_/668370", "title"=>"List of biological functions of the 291 genes whose expression was influenced by vitamin D<sub>3</sub> supplementation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-20 02:19:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/993150", "https://ndownloader.figshare.com/files/993151", "https://ndownloader.figshare.com/files/993153", "https://ndownloader.figshare.com/files/993155", "https://ndownloader.figshare.com/files/993156", "https://ndownloader.figshare.com/files/993160", "https://ndownloader.figshare.com/files/993161", "https://ndownloader.figshare.com/files/993163", "https://ndownloader.figshare.com/files/993164"], "description"=>"<div><p>Background</p><p>Although there have been numerous observations of vitamin D deficiency and its links to chronic diseases, no studies have reported on how vitamin D status and vitamin D<sub>3</sub> supplementation affects broad gene expression in humans. The objective of this study was to determine the effect of vitamin D status and subsequent vitamin D supplementation on broad gene expression in healthy adults. (Trial registration: ClinicalTrials.gov NCT01696409).</p> <p>Methods and Findings</p><p>A randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D<sub>3</sub> daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults in the winter. Microarrays of the 16 buffy coats from eight subjects passed the quality control filters and normalized with the RMA method. Vitamin D<sub>3</sub> supplementation that improved serum 25-hydroxyvitamin D concentrations was associated with at least a 1.5 fold alteration in the expression of 291 genes. There was a significant difference in the expression of 66 genes between subjects at baseline with vitamin D deficiency (25(OH)D<20 ng/ml) and subjects with a 25(OH)D>20 ng/ml. After vitamin D<sub>3</sub> supplementation gene expression of these 66 genes was similar for both groups. Seventeen vitamin D-regulated genes with new candidate vitamin D response elements including TRIM27, CD83, COPB2, YRNA and CETN3 which have been shown to be important for transcriptional regulation, immune function, response to stress and DNA repair were identified.</p> <p>Conclusion/Significance</p><p>Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D.</p> <p>Trial Registration</p><p>ClinicalTrials.gov <a href=\"http://clinicaltrials.gov/ct2/show/NCT01696409\" target=\"_blank\">NCT01696409</a></p> </div>", "links"=>[], "tags"=>["supplementation", "genome", "randomized", "double-blind", "trial"], "article_id"=>656671, "categories"=>["Chemistry", "Hematology", "Biotechnology", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Arash Hossein-nezhad", "Avrum Spira", "Michael F. Holick"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0058725.s001", "https://dx.doi.org/10.1371/journal.pone.0058725.s002", "https://dx.doi.org/10.1371/journal.pone.0058725.s003", "https://dx.doi.org/10.1371/journal.pone.0058725.s004", "https://dx.doi.org/10.1371/journal.pone.0058725.s005", "https://dx.doi.org/10.1371/journal.pone.0058725.s006", "https://dx.doi.org/10.1371/journal.pone.0058725.s007", "https://dx.doi.org/10.1371/journal.pone.0058725.s008", "https://dx.doi.org/10.1371/journal.pone.0058725.s009"], "stats"=>{"downloads"=>126, "page_views"=>65, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Influence_of_Vitamin_D_Status_and_Vitamin_D_3_Supplementation_on_Genome_Wide_Expression_of_White_Blood_Cells_A_Randomized_Double_Blind_Clinical_Trial__/656671", "title"=>"Influence of Vitamin D Status and Vitamin D<sub>3</sub> Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-03-21 04:38:33"}

PMC Usage Stats | Further Information

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Relative Metric

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