학술논문
Plasma cortisol-linked gene networks in hepatic and adipose tissues implicate corticosteroid-binding globulin in modulating tissue glucocorticoid action and cardiovascular risk.
Document Type
Academic Journal
Author
Bankier S; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.; Division of Genetics and Genomics, The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom.; Wang L; Division of Genetics and Genomics, The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom.; Crawford A; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.; Morgan RA; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; SRUC, The Roslin Institute, Edinburgh, United Kingdom.; Ruusalepp A; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.; Department of Cardiology, Institute of Clinical Medicine, Tartu University, Tartu, Estonia.; Clinical Gene Networks AB, Stockholm, Sweden.; Andrew R; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Björkegren JLM; Clinical Gene Networks AB, Stockholm, Sweden.; Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.; Walker BR; University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Clinical and Translational Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.; Michoel T; Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.; Division of Genetics and Genomics, The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101555782 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2392 (Print) Linking ISSN: 16642392 NLM ISO Abbreviation: Front Endocrinol (Lausanne) Subsets: MEDLINE
Subject
Language
English
ISSN
1664-2392
Abstract
Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 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, IRF2 . 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.
Competing Interests: Authors JB and AR was employed by the company Clinical Gene Networks AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Bankier, Wang, Crawford, Morgan, Ruusalepp, Andrew, Björkegren, Walker and Michoel.)
Competing Interests: Authors JB and AR was employed by the company Clinical Gene Networks AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Bankier, Wang, Crawford, Morgan, Ruusalepp, Andrew, Björkegren, Walker and Michoel.)