{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:09:42Z","timestamp":1715645382140},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator\u2013activated receptor \u03b3 (PPAR\u03b3) that is involved in lipid and glucose metabolism and maintenance of metabolic homeostasis. We used a functional genomics methodology to interrogate human chromatin immunoprecipitation-sequencing, genome-wide association studies, and expression quantitative trait locus data to inform selection of candidate functional single nucleotide polymorphisms (SNPs) falling in PPAR\u03b3 motifs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>We derived 27 328 chromatin immunoprecipitation-sequencing peaks for PPAR\u03b3 in human adipocytes through meta-analysis of 3 data sets. The PPAR\u03b3 consensus motif showed greatest enrichment and mapped to 8637 peaks. We identified 146 SNPs in these motifs. This number was significantly less than would be expected by chance, and Inference of Natural Selection from Interspersed Genomically coHerent elemenTs analysis indicated that these motifs are under weak negative selection. A screen of these SNPs against genome-wide association studies for cardiometabolic traits revealed significant enrichment with 16 SNPs. A screen against the MuTHER expression quantitative trait locus data revealed 8 of these were significantly associated with altered gene expression in human adipose, more than would be expected by chance. Several SNPs fall close, or are linked by expression quantitative trait locus to lipid-metabolism loci including CYP26A1.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>We demonstrated the use of functional genomics to identify SNPs of potential function. Specifically, that SNPs within PPAR\u03b3 motifs that bind PPAR\u03b3 in adipocytes are significantly associated with cardiometabolic disease and with the regulation of transcription in adipose. This method may be used to uncover functional SNPs that do not reach significance thresholds in the agnostic approach of genome-wide association studies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.115.001174","type":"journal-article","created":{"date-parts":[[2015,10,31]],"date-time":"2015-10-31T02:59:28Z","timestamp":1446260368000},"page":"842-851","update-policy":"http:\/\/dx.doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Functional Genomics Analysis of Big Data Identifies Novel Peroxisome Proliferator\u2013Activated Receptor \u03b3 Target Single Nucleotide Polymorphisms Showing Association With Cardiometabolic Outcomes"],"prefix":"10.1161","volume":"8","author":[{"given":"Kris","family":"Richardson","sequence":"first","affiliation":[{"name":"From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin R.","family":"Schnitzler","sequence":"additional","affiliation":[{"name":"From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Qiang","family":"Lai","sequence":"additional","affiliation":[{"name":"From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose M.","family":"Ordovas","sequence":"additional","affiliation":[{"name":"From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid,..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20579"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0710-551"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2011.00640.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0508-489"},{"key":"e_1_3_3_6_2","first-page":"57","article-title":"An integrated encyclopedia of DNA elements in the human genome.","volume":"488","author":"Consortium TEP, Consortium TEP, Data Analysis Coordination OC, Data Production DPL, Data Analysis LA, Group W","year":"2013","unstructured":"Consortium TEP, Consortium TEP, Data Analysis Coordination OC, Data Production DPL, Data Analysis LA, Group W, , et al.. An integrated encyclopedia of DNA elements in the human genome. Nature. 2013;488:57\u201374.","journal-title":"Nature"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09534"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1129"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2394"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2797"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14177"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14132"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2274"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.012"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-504"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.000738"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3159"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2004.tb00058.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1323-1"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.09.006"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0454"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1193"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-2-r11"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr189"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M500504-JLR200"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt997"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1196"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr064"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq707"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3715005"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mst019"},{"key":"e_1_3_3_35_2","volume-title":"qvalue: Q-value estimation for false discovery rate control","author":"Dabney A","unstructured":"Dabney A, Storey JD. qvalue: Q-value estimation for false discovery rate control. R package version 1.36.0 2013."},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu655"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth457"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1630"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt989"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-152"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1709008"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1225057"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2658"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.32.20108"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.27.16114"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004525"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051268"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-7-r147"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2011.06.001"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-008-0196-z"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010693"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M037085"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.06.025"}],"container-title":["Circulation: Cardiovascular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGENETICS.115.001174","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:32:29Z","timestamp":1715563949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGENETICS.115.001174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12]]},"references-count":52,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,12]]}},"alternative-id":["10.1161\/CIRCGENETICS.115.001174"],"URL":"https:\/\/doi.org\/10.1161\/circgenetics.115.001174","relation":{},"ISSN":["1942-325X","1942-3268"],"issn-type":[{"value":"1942-325X","type":"print"},{"value":"1942-3268","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12]]}}}