Genome-Wide Analysis of DNA Methylation Differences in Muscle and Fat from Monozygotic Twins Discordant for Type 2 Diabetes
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{"title"=>"Genome-Wide Analysis of DNA Methylation Differences in Muscle and Fat from Monozygotic Twins Discordant for Type 2 Diabetes", "type"=>"journal", "authors"=>[{"first_name"=>"Rasmus", "last_name"=>"Ribel-Madsen", "scopus_author_id"=>"26424355200"}, {"first_name"=>"Mario F.", "last_name"=>"Fraga", "scopus_author_id"=>"7005319930"}, {"first_name"=>"Stine", "last_name"=>"Jacobsen", "scopus_author_id"=>"56223340700"}, {"first_name"=>"Jette", "last_name"=>"Bork-Jensen", "scopus_author_id"=>"36597911800"}, {"first_name"=>"Ester", "last_name"=>"Lara", "scopus_author_id"=>"25624744400"}, {"first_name"=>"Vincenzo", "last_name"=>"Calvanese", "scopus_author_id"=>"25624346100"}, {"first_name"=>"Agustin F.", "last_name"=>"Fernandez", "scopus_author_id"=>"7403494648"}, {"first_name"=>"Martin", "last_name"=>"Friedrichsen", "scopus_author_id"=>"26424224800"}, {"first_name"=>"Birgitte F.", "last_name"=>"Vind", "scopus_author_id"=>"16403772100"}, {"first_name"=>"Kurt", "last_name"=>"Højlund", "scopus_author_id"=>"6603935402"}, {"first_name"=>"Henning", "last_name"=>"Beck-Nielsen", "scopus_author_id"=>"7102424554"}, {"first_name"=>"Manel", "last_name"=>"Esteller", "scopus_author_id"=>"14719291800"}, {"first_name"=>"Allan", "last_name"=>"Vaag", "scopus_author_id"=>"7006759757"}, {"first_name"=>"Pernille", "last_name"=>"Poulsen", "scopus_author_id"=>"7102175750"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84870923467", "sgr"=>"84870923467", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0051302", "pmid"=>"23251491", "isbn"=>"1932-6203 (Electronic) 1932-6203 (Linking)", "pui"=>"366250895"}, "id"=>"cd6b1aa9-00a9-307a-aa02-ccdd2d6737fd", "abstract"=>"BackgroundMonozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins.Methodology/Principal FindingsSkeletal muscle (n = 11 pairs) and subcutaneous adipose tissue (n = 5 pairs) biopsies were collected from 53–80 year-old monozygotic twin pairs discordant for type 2 diabetes. DNA methylation was measured by microarrays at 26,850 cytosine-guanine dinucleotide (CpG) sites in the promoters of 14,279 genes. Bisulfite sequencing was applied to validate array data and to quantify methylation of intergenic repetitive DNA sequences. The overall intra-pair variation in DNA methylation was large in repetitive (LINE1, D4Z4 and NBL2) regions compared to gene promoters (standard deviation of intra-pair differences: 10% points vs. 4% points, P<0.001). Increased variation of LINE1 sequence methylation was associated with more phenotypic dissimilarity measured as body mass index (r = 0.77, P = 0.007) and 2-hour plasma glucose (r = 0.66, P = 0.03) whereas the variation in promoter methylation did not associate with phenotypic differences. Validated methylation changes were identified in the promoters of known type 2 diabetes-related genes, including PPARGC1A in muscle (13.9±6.2% vs. 9.0±4.5%, P = 0.03) and HNF4A in adipose tissue (75.2±3.8% vs. 70.5±3.7%, P<0.001) which had increased methylation in type 2 diabetic individuals. A hypothesis-free genome-wide exploration of differential methylation without correction for multiple testing identified 789 and 1,458 CpG sites in skeletal muscle and adipose tissue, respectively. These methylation changes only reached some percentage points, and few sites passed correction for multiple testing.Conclusions/SignificanceOur study suggests that likely acquired DNA methylation changes in skeletal muscle or adipose tissue gene promoters are quantitatively small between type 2 diabetic and non-diabetic twins. The importance of methylation changes in candidate genes such as PPARGC1A and HNF4A should be examined further by replication in larger samples.", "link"=>"http://www.mendeley.com/research/genomewide-analysis-dna-methylation-differences-muscle-fat-monozygotic-twins-discordant-type-2-diabe", "reader_count"=>79, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Student > Doctoral Student"=>7, "Researcher"=>15, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>6, "Other"=>3, "Student > Master"=>7, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Student > Doctoral Student"=>7, "Researcher"=>15, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>6, "Other"=>3, "Student > Master"=>7, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>18, "Agricultural and Biological Sciences"=>38, "Medicine and Dentistry"=>14, "Neuroscience"=>1, "Sports and Recreations"=>3, "Social Sciences"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Neuroscience"=>{"Neuroscience"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>38}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>18}, "Unspecified"=>{"Unspecified"=>2}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"Korea (South)"=>1, "Brazil"=>1, "South Africa"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/285381", "https://ndownloader.figshare.com/files/285441", "https://ndownloader.figshare.com/files/285490"], "description"=>"<div><h3>Background</h3><p>Monozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins.</p> <h3>Methodology/Principal Findings</h3><p>Skeletal muscle (<em>n</em> = 11 pairs) and subcutaneous adipose tissue (<em>n</em> = 5 pairs) biopsies were collected from 53–80 year-old monozygotic twin pairs discordant for type 2 diabetes. DNA methylation was measured by microarrays at 26,850 cytosine-guanine dinucleotide (CpG) sites in the promoters of 14,279 genes. Bisulfite sequencing was applied to validate array data and to quantify methylation of intergenic repetitive DNA sequences. The overall intra-pair variation in DNA methylation was large in repetitive (LINE1, D4Z4 and NBL2) regions compared to gene promoters (standard deviation of intra-pair differences: 10% points vs. 4% points, <em>P</em><0.001). Increased variation of LINE1 sequence methylation was associated with more phenotypic dissimilarity measured as body mass index (r = 0.77, <em>P</em> = 0.007) and 2-hour plasma glucose (r = 0.66, <em>P</em> = 0.03) whereas the variation in promoter methylation did not associate with phenotypic differences. Validated methylation changes were identified in the promoters of known type 2 diabetes-related genes, including <em>PPARGC1A</em> in muscle (13.9±6.2% vs. 9.0±4.5%, <em>P</em> = 0.03) and <em>HNF4A</em> in adipose tissue (75.2±3.8% vs. 70.5±3.7%, <em>P</em><0.001) which had increased methylation in type 2 diabetic individuals. A hypothesis-free genome-wide exploration of differential methylation without correction for multiple testing identified 789 and 1,458 CpG sites in skeletal muscle and adipose tissue, respectively. These methylation changes only reached some percentage points, and few sites passed correction for multiple testing.</p> <h3>Conclusions/Significance</h3><p>Our study suggests that likely acquired DNA methylation changes in skeletal muscle or adipose tissue gene promoters are quantitatively small between type 2 diabetic and non-diabetic twins. The importance of methylation changes in candidate genes such as <em>PPARGC1A</em> and <em>HNF4A</em> should be examined further by replication in larger samples.</p> </div>", "links"=>[], "tags"=>["genome-wide", "dna", "methylation", "differences", "monozygotic", "twins", "discordant", "diabetes"], "article_id"=>116251, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.s001", "https://dx.doi.org/10.1371/journal.pone.0051302.s002", "https://dx.doi.org/10.1371/journal.pone.0051302.s003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genome_Wide_Analysis_of_DNA_Methylation_Differences_in_Muscle_and_Fat_from_Monozygotic_Twins_Discordant_for_Type_2_Diabetes__/116251", "title"=>"Genome-Wide Analysis of DNA Methylation Differences in Muscle and Fat from Monozygotic Twins Discordant for Type 2 Diabetes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-12-10 01:44:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/528116"], "description"=>"<p>Plasma glucose 120 min after a 75-g oral glucose load in type 2 diabetic and non-diabetic twins (<i>n</i> = 12 pairs, <i>P</i><0.001). <b>B</b> Glucose infusion rate during a euglycemic-hyperinsulinemic clamp in type 2 diabetic and non-diabetic twins (<i>n</i> = 9 pairs, <i>P</i> = 0.006). Data are presented as mean±standard error of the mean.</p>", "links"=>[], "tags"=>["glucose", "insulin", "monozygotic"], "article_id"=>198596, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Discordance_for_oral_glucose_tolerance_and_insulin_sensitivity_in_monozygotic_twins_A_/198596", "title"=>"Discordance for oral glucose tolerance and insulin sensitivity in monozygotic twins. A", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-10 02:23:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/528214"], "description"=>"<p>The DNA methylation was measured as the β-value ranging from 0 (unmethylated) to 1 (completely methylated) at 26,850 CpG sites located in the promoters of 14,279 genes. The plots are shown for a representative twin pair (#3). <b>A</b> Skeletal muscle (r = 0.95, <i>P</i><0.001). <b>B</b> SAT (r = 0.97, <i>P</i><0.001). <b>C</b> Comparison of DNA methylation in SAT and skeletal muscle from the non-diabetic twin.</p>", "links"=>[], "tags"=>["promoter", "dna", "methylation", "monozygotic"], "article_id"=>198696, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Global_gene_promoter_DNA_methylation_in_monozygotic_twins_/198696", "title"=>"Global gene promoter DNA methylation in monozygotic twins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-10 02:24:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/528483"], "description"=>"<p>The variation is given by the standard deviation (SD) of the absolute methylation differences between monozygotic twins in skeletal muscle. <b>A</b> SD of methylation differences on all repetitive versus all promoter CpG sites (r = −0.05, <i>P</i> = 0.9). <b>B</b> SD of methylation differences on LINE1 repetitive CpG sites versus absolute difference in BMI (r = 0.77, <i>P</i> = 0.007). <b>C</b> SD of methylation differences on LINE1 repetitive CpG sites versus absolute difference in 2-hour plasma glucose (r = 0.66, <i>P</i> = 0.03). <b>D</b> SD of methylation differences on LINE1 repetitive CpG sites versus absolute difference in glucose infusion rate (r = 0.52, <i>P</i> = 0.2).</p>", "links"=>[], "tags"=>["dna", "methylation", "repetitive"], "article_id"=>198964, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intra_twin_pair_variation_of_DNA_methylation_in_repetitive_DNA_sequences_/198964", "title"=>"Intra-twin pair variation of DNA methylation in repetitive DNA sequences.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-10 02:29:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/528630"], "description"=>"<p>Data are shown as mean±standard deviation.</p>", "links"=>[], "tags"=>["monozygotic", "twins", "discordant"], "article_id"=>199110, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_monozygotic_twins_discordant_for_type_2_diabetes_/199110", "title"=>"Characteristics of monozygotic twins discordant for type 2 diabetes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-10 02:31:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/528675"], "description"=>"<p>The 20 CpG sites with the lowest <i>P</i>-values for the intra-pair methylation difference between type 2 diabetic and non-diabetic twins are shown for subcutaneous adipose tissue and skeletal muscle. The total number of differentially methylated CpG sites, without correction for multiple testing, was 1,458 in subcutaneous adipose tissue and 789 in skeletal muscle. Each CpG site is identified with Illumina probe target ID. The CpG site location is given as the base pair distance to transcription start site (TSS) if available. Data are shown as mean±standard deviation. <i>P</i><sub>adj</sub>-values are corrected for multiple testing (26,850 tests).</p>", "links"=>[], "tags"=>["methylated"], "article_id"=>199160, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.t003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differentially_methylated_genes_/199160", "title"=>"Differentially methylated genes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-10 02:32:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/528710"], "description"=>"<p>The microarray included in total 49 type 2 diabetes candidate genes represented by 136 probes. Each CpG site is identified with Illumina probe target ID. The CpG site location is given as the base pair distance to transcription start site (TSS) if available. Data are shown as mean±standard deviation. <i>P</i><sub>adj</sub>-values are corrected for multiple testing (136 tests).</p>", "links"=>[], "tags"=>["methylated", "susceptibility"], "article_id"=>199193, "categories"=>["Chemistry", "Biochemistry", "Biophysics", "Physiology", "Biological Sciences", "Genetics"], "users"=>["Rasmus Ribel-Madsen", "Mario F. Fraga", "Stine Jacobsen", "Jette Bork-Jensen", "Ester Lara", "Vincenzo Calvanese", "Agustin F. Fernandez", "Martin Friedrichsen", "Birgitte F. Vind", "Kurt Højlund", "Henning Beck-Nielsen", "Manel Esteller", "Allan Vaag", "Pernille Poulsen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051302.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differentially_methylated_type_2_diabetes_susceptibility_genes_/199193", "title"=>"Differentially methylated type 2 diabetes susceptibility genes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-10 02:33:13"}

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Relative Metric

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