Cortisol-responsive gene networks in cardiovascular disease

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

Project Summary:
Cardiovascular disease (CVD) is influenced by genetic, environmental and metabolic factors which govern both its onset and severity. One such factor is the activity of glucocorticoids such as cortisol which influences CVD risk factors such as hypertension, obesity and type II diabetes. The CORtisol NETwork (CORNET) consortium undertook a genome wide association meta-analysis to identify genetic variants that are associated with changes in levels of plasma cortisol (Bolton et al, 2014). Mendelian randomisation has then been used to demonstrate that these variants are causative for CVD, however the mechanism by which these variants exert an effect upon CVD risk is poorly understood. There is the potential to elucidate these mechanisms by examining gene expression in the tissues that are affected by CVD.
The Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET) sequenced and genotyped vascular and metabolic tissue from 600 CVD patients. This resource has the potential to be used to study gene regulatory risk variants for cardio-metabolic disease (Franzén et al, 2016). A recent investigation in the first 100 study participants illustrates that through the use of statistical learning algorithms, causal networks can be identified that link genetic variation to variation in expression of hundreds of genes to variation in clinical characteristics of patients (Talukdar et al, 2016). However, this requires the development of systematic methods to design therapeutic strategies that allow for the precision control of these networks in order to achieve translational benefit from this research.
This project will utilise a systems and synthetic biology approach to identify tissue-specific gene networks that are affected by risk variants for plasma cortisol through use of the CORNET and STARNET datasets. In addition, an in vitro model system allowing for real time control for these networks will be developed. As most variation in plasmacortisol is mediated through nuclear hormone receptors and therefore through changes in transcription, it is expected that this approach will be highly applicable to Glucocorticoid biology.



Aims:

- To identify tissue specific gene networks that are affected by genetic variation for changes in plasma cortisol levels and causally associated with cardiovascular disease phenotypes and type II diabetes. This will be achieved through use of the STARNET dataset and use of modern causal inference methods.

- To predict the effect of nuclear hormone receptor activity, known inhibitors of cortisol activity and other pharmacologic compounds on the activity of these networks by mining publicly available expression databases in GEO/ ArrayExpress.

- To genetically engineer an appropriate cell line to tag a master regulator of a selected network with a fluorescent reporter, and use optimal (feedback) control (Menolascina et al, 2014) to determine the best therapy (sequence of drugs and their concentrations) to control the activity of this regulator.

- To validate the predicated effect of the optimal treatment on network activity and cell phenotypic variables by a differential expression experiment in the same in vitro model.

References:

Bolton JL, et al. (2014). Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin. PLoS Genet. 10(7), e1004474.
Franzén O, et al. (2016). Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science; 353(6301), 827-830.
Menolascina F, et al. (2014) In-vivo real-time control of protein expression from endogenous and synthetic gene networks. PLoS Comput Biol. 10(5), e1003625.
Talukdar H, et al. (2016). Cross-tissue regulatory gene networks in coronary artery disease. Cell Systems. 2(3), 196-208.

Publications

10 25 50
 
Description Cortisol Network (CORNET) consortium 
Organisation Cortisol Network (CORNET)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I undertook analysis, linking genetic variants associated with plasma cortisol to changes in gene expression as expression Quantitative Trait Loci (eQTLs). I also performed colocalisation analysis between the cortisol and eQTL signals. This work is currently being complied as a manuscript to which I have contributed and hold a position of co-first author.
Collaborator Contribution CORNET was established with the initial aim of identifying genetic determinants of inter-individual variation in HPA axis function. The CORNET consortium extended its genome-wide association meta-analysis (GWAMA) for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2M to ~7M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. No new loci were identified. Expression quantitative trait loci (eQTL) analyses undertaken in STARNET, showing that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Collaborators at The University of Bristol carried out the GWAMA and conducted Mendelian Randomisation (MR) analysis. Additional consortium members contributed cohorts to the analysis.
Impact - A manuscript is currently in preparation which will report the latest findings previously stated. The work reported from this publication provides the groundwork for further downstream analysis that is currently being conducted. This is a collaboration between geneticists, epidemiologists and endocrinologists.
Start Year 2017
 
Description Article in The Biochemist Blog 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I wrote an article in The Biochemist Blog, an offshoot of "The Biochemist", the official website of The Biochemical Society. The article used language that could be understood by a general audience.
Year(s) Of Engagement Activity 2019
URL https://thebiochemistblog.com/2019/01/23/biometricians-vs-mendelians-what-a-century-old-debate-ago-c...
 
Description Cafe Synthetique 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact I was a founding member of the organisation Cafe Synthetique which aims to bring discussion of synthetic biology to a specialist and general audience through monthly events. These events include workshops and discussions with invited speakers and take place in a relaxed atmosphere to stimulate discussion. My role was hosting these sessions until I stepped down in late 2019.
Year(s) Of Engagement Activity 2018,2019
URL https://www.cafesynthetique.com/
 
Description Midlothian Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Researchers from the University of Edinburgh Centre for Cardiovascular Science attended the Midlothian Science Festival and hosted the event "stress busters". This was aimed at a general audience with activities catered to children of primary school age. The activity helped to describe to children the biological effects of stress and understanding the impact that cortisol has on the human body and in other animals.
Year(s) Of Engagement Activity 2019