{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:33:46Z","timestamp":1776274426858,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["1938124"],"award-info":[{"award-number":["1938124"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107049\/Z\/15\/Z"],"award-info":[{"award-number":["107049\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["312045"],"award-info":[{"award-number":["312045"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the\n                    <jats:italic>SERPINA6\/SERPINA1<\/jats:italic>\n                    locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and\n                    <jats:italic>SERPINA6<\/jats:italic>\n                    mRNA expression encoding corticosteroid-binding globulin (CBG) in the liver. These and other findings indicate that higher plasma cortisol levels are causally associated with CVD; however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol-linked single-nucleotide polymorphisms (SNPs) that are trans-associated with genes from seven different vascular and metabolic tissues, finding the highest representation of trans-genes in the liver, subcutaneous fat, and visceral abdominal fat, [false discovery rate (FDR) = 15%]. We identified a subset of cortisol-associated trans-genes that are putatively regulated by the glucocorticoid receptor (GR), the primary transcription factor activated by cortisol. Using causal inference, we identified GR-regulated trans-genes that are responsible for the regulation of tissue-specific gene networks. Cis-expression Quantitative Trait Loci (eQTLs) were used as genetic instruments for identification of pairwise causal relationships from which gene networks could be reconstructed. Gene networks were identified in the liver, subcutaneous fat, and visceral abdominal fat, including a high confidence gene network specific to subcutaneous adipose (FDR = 10%) under the regulation of the interferon regulatory transcription factor,\n                    <jats:italic>IRF2<\/jats:italic>\n                    . These data identify a plausible pathway through which variation in the liver CBG production perturbs cortisol-regulated gene networks in peripheral tissues and thereby promote CVD.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2023.1186252","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T13:45:41Z","timestamp":1694007941000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Plasma cortisol-linked gene networks in hepatic and adipose tissues implicate corticosteroid-binding globulin in modulating tissue glucocorticoid action and cardiovascular risk"],"prefix":"10.3389","volume":"14","author":[{"given":"Sean","family":"Bankier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth A.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arno","family":"Ruusalepp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Andrew","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan L. M.","family":"Bj\u00f6rkegren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian R.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Michoel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-07-0455","article-title":"Glucocorticoids and cardiovascular disease","volume":"157","author":"Walker","year":"2007","journal-title":"Eur J Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1113\/jphysiol.2014.282871","article-title":"Cushing\u2019s syndrome: from physiological principles to diagnosis and clinical care","volume":"593","author":"Raff","year":"2015","journal-title":"J Physiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)68699-6","article-title":"Cushing\u2019s syndrome","volume":"367","author":"Newell-Price","year":"2006","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/0039-128X(94)00033-9","article-title":"Mechanisms of cortisol-induced hypertension in humans","volume":"60","author":"Whitworth","year":"1995","journal-title":"Steroids Aldosterone Hypertension"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-1267","article-title":"Cortisol Secretion in Patients With Type 2 Diabetes: Relationship with chronic complications","author":"Chiodini","year":"2007","journal-title":"Diabetes Care"},{"key":"B6","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1023\/A:1025321609994","article-title":"Heritability of daytime cortisol levels in children","author":"Bartels","year":"2003","journal-title":"Behav Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004474","article-title":"Genome wide association identifies common variants at the SERPINA6\/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin","author":"Bolton","year":"2014","journal-title":"PloS Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s10038-020-00895-6","article-title":"Variation in the SERPINA6\/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease","author":"Crawford","year":"2021","journal-title":"J Hum Genet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1210\/edrv-11-1-65","article-title":"Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins*","author":"Hammond","year":"1990","journal-title":"Endocrine Rev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.134","article-title":"Regulation of cortisol bioavailability\u2014effects on hormone measurement and action","author":"Perogamvros","year":"2012","journal-title":"Nat Rev Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6196","DOI":"10.1038\/336257a0","article-title":"Hormone binding globulins undergo serpin conformational change in inflammation","volume":"336","author":"Pemberton","year":"1988","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4280","article-title":"How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration","author":"Chan","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cca.2015.10.028","article-title":"Corticosteroid binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: Implications for cortisol homeostasis","volume":"452","author":"Nenke","year":"2016","journal-title":"Clinica Chimica Acta"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccn.2005.03.044","article-title":"Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin","author":"Lewis","year":"2005","journal-title":"Clinica Chimica Acta"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.09.007","article-title":"The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease","author":"Oakley","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.8.7724","article-title":"Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension","author":"Torpy","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-006-0620-5","article-title":"Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency","author":"Buss","year":"2007","journal-title":"J Neural Transm"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3130","article-title":"Naturally occurring mutations of human corticosteroid-binding globulin","author":"Simard","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad6970","article-title":"Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases","author":"Franz\u00e9n","year":"2016","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.cels.2016.02.002","article-title":"Cross-tissue regulatory gene networks in coronary artery disease","author":"Talukdar","year":"2016","journal-title":"Cell Syst"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.O072629","article-title":"The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases","author":"Laakso","year":"2017","journal-title":"J Lipid Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005703","article-title":"Efficient and accurate causal inference with hidden confounders from genome-transcriptome variation data","author":"Wang","year":"2017","journal-title":"PloS Comput Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015188","article-title":"Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis","author":"Yu","year":"2010","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"101225","DOI":"10.1016\/j.molmet.2021.101225","article-title":"Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice","volume":"48","author":"Bell","year":"2021","journal-title":"Mol Metab"},{"key":"B25","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nature11233","article-title":"Landscape of transcription in human cells","author":"Djebali","year":"2012","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg108","article-title":"TRANSFAC \u00ae : transcriptional regulation, from patterns to profiles","author":"Matys","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq466","article-title":"ChEA: transcription factor regulation inferred from integrating genome wide ChIP-X experiments","author":"Lachmann","year":"2010","journal-title":"Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: fundamental algorithms for scientific computing in Python","author":"Virtanen","year":"2020","journal-title":"Nat Methods"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: statistical data visualization","author":"Waskom","year":"2021","journal-title":"J Open Source Softw"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: regional visualization of genome-wide association scan results","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S247379","article-title":"Glucocorticoid-induced fatty liver disease","volume":"13","author":"Rahimi","year":"2020","journal-title":"Diab Metab Syndr Obesity: Targets Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.572981","article-title":"Multifaceted control of GR signaling and its impact on hepatic transcriptional networks and metabolism","volume":"11","author":"Pr\u00e6stholm","year":"2020","journal-title":"English. Front Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/oby.20073","article-title":"Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects","author":"Pavlatou","year":"2013","journal-title":"Obesity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.32527\/2018\/101373","article-title":"Glucocorticoid receptor and adipocyte biology","volume":"5","author":"Lee","year":"2018","journal-title":"Nucl receptor Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.810127","article-title":"Splice variants of cytosolic polyadenylation element\u2013binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis","author":"DeLigio","year":"2017","journal-title":"J Biol Chem"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4834","article-title":"CD163 and inflammation: biological, diagnostic, and therapeutic aspects","author":"Etzerodt","year":"2013","journal-title":"Antioxid Redox Signaling"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.044495","article-title":"The role of RBM25\/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure","author":"Gao","year":"2011","journal-title":"Circulation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"36741","DOI":"10.1038\/srep36741","article-title":"LUC7L3\/CROP inhibits replication of hepatitis B virus via suppressing enhancer II\/basal core promoter activity","author":"Li","year":"2016","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.368829","article-title":"RNF13, a RING Finger Protein, Mediates Endoplasmic Reticulum Stress induced Apoptosis through the Inositol-requiring Enzyme (IRE1\u03b1)\/c-Jun NH2-terminal Kinase Pathway","author":"Arshad","year":"2013","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.8438157","article-title":"Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2","author":"Harada","year":"1993","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000116","article-title":"Peripheral blood IRF1 expression as a marker for glucocorticoid sensitivity","author":"Chapin","year":"2015","journal-title":"Pharmacogenetics Genomics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309344","article-title":"LIPA variants in genome-wide association studies of coronary artery diseases","author":"Zhang","year":"2017","journal-title":"Arteriosclerosis Thrombosis Vasc Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.302709","article-title":"Lim domain binding 2","author":"Shang","year":"2014","journal-title":"Arteriosclerosis Thrombosis Vasc Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1677\/jme.1.02048","article-title":"Expression profiling of 11beta-hydroxysteroid dehydrogenase type-1 and glucocorticoid target genes in subcutaneous and omental human preadipocytes","author":"Bujalska","year":"2006","journal-title":"J Mol Endocrinol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa002","article-title":"Dynamics of ACTH and cortisol secretion and implications for disease","author":"Lightman","year":"2020","journal-title":"Endocrine Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/0148607113496117","article-title":"The surgically induced stress response","author":"Finnerty","year":"2013","journal-title":"JPEN. J parenteral enteral Nutr"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004818","article-title":"Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: A genome-wide analysis among 1,800 South Asians","author":"Pierce","year":"2014","journal-title":"PloS Genet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2133841100","article-title":"Structure and function of the feed-forward loop network motif","author":"Mangan","year":"2003","journal-title":"Proc Natl Acad Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.9.4833","article-title":"Inhibition of IFN-\u03b3 Signaling by glucocorticoids","author":"Hu","year":"2003","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00146-10","article-title":"The type I interferon signaling pathway is a target for glucocorticoid inhibition","author":"Flammer","year":"2010","journal-title":"Mol Cell Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070919","article-title":"Stochastic gene expression in a single cell","author":"Elowitz","year":"2002","journal-title":"Science"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1186252\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T13:45:45Z","timestamp":1694007945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1186252\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,6]]},"references-count":51,"alternative-id":["10.3389\/fendo.2023.1186252"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1186252","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.01.20.524857","asserted-by":"object"}]},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,6]]},"article-number":"1186252"}}