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Cited by 74Genetic Associations and EpidemiologyStress Responses and CortisolAdrenal Hormones and Disorders

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

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Crawford, Andrew A., Bankier, Sean, Altmaier, Elisabeth, Barnes, Catriona L. K., Clark, David W., Ermel, Raili, Friedrich, Nele, van der Harst, Pim +34 more·2021·Journal of Human Genetics
DOI 10.1038/s10038-020-00895-6PMC PMC8144017
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Abstract

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1 . This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

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Authors
Crawford, A. A., Bankier, S., Altmaier, E., Barnes, C. L. K., Clark, D. W., Ermel, R., Friedrich, N., van der Harst, P., Joshi, P. K., Karhunen, V., Lahti, J., Mahajan, A., Mangino, M., Nethander, M., Neumann, A., Pietzner, M., Sukhavasi, K., Wang, C. A., Bakker, S. J. L., Bjorkegren, J. L. M., Campbell, H., Eriksson, J., Gieger, C., Hayward, C., Jarvelin, M.-R., McLachlan, S., Morris, A. P., Ohlsson, C., Pennell, C. E., Price, J., Rudan, I., Ruusalepp, A., Spector, T., Tiemeier, H., Völzke, H., Wilson, J. F., Michoel, T., Timpson, N. J., Smith, G. D., Walker, B. R., on behalf of the CORtisol NETwork (CORNET) consortium, & Mellström, D.
Affiliations
  • University of Bristol (GB)
  • Roslin Institute (GB)
  • Helmholtz Munich (DE)
  • University of Edinburgh (GB)
  • Tartu University Hospital (EE)
  • Universitätsmedizin Greifswald (DE)
  • Public Health England (GB)
  • University of Helsinki (FI)
  • Centre for Human Genetics (GB)
  • King's College London (GB)
  • University of Gothenburg (SE)
  • Jewish General Hospital (CA)
  • University of Newcastle Australia (AU)
  • University Medical Center Groningen (NL)
  • Western General Hospital (GB)
  • Sahlgrenska University Hospital (SE)
  • Guy's and St Thomas' NHS Foundation Trust (GB)
  • Harvard University (US)
  • The Queen's Medical Research Institute (GB)
Corresponding author
Walker, Brian R.
ORCID
Venue
Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-01-20
Volume
66
Issue
6
Pages
625-636
ISSN
  • 1434-5161 (ISSN-L)
  • 1435-232X
DOI
10.1038/s10038-020-00895-6
PMC
PMC8144017
OpenAlex
W3111421261
Cited by
74
References
9
Citations by year
2026: 13 · 2025: 13 · 2024: 16 · 2023: 13 · 2022: 11 · 2021: 8
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • UTUPub (University of Turku) (submittedVersion, cc-by)
  • National University of Singapore (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • NOVA (University of Newcastle Australia) (submittedVersion, cc-by)
Funders
  • RCUK | Medical Research Council (1938124)
  • British Heart Foundation (RG/11/4/28734)
  • Wellcome Trust (107049/Z/15/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
corticosteroid-binding globulin, alpha-1-antitrypsin, genetic variants, expression quantitative trait loci, trans-eQTL, hepatic gene expression, adipose tissue gene expression, ischemic heart disease, myocardial infarction, cardiovascular risk, stress hormones, Mendelian randomization
MeSH terms
Adrenal Cortex Hormones, Adult, alpha 1-Antitrypsin, Cardiovascular Diseases, Female, Gene Expression Regulation, United Kingdom, Humans, Liver, Male, Middle Aged, Myocardial Infarction, Transcortin, Biological Specimen Banks, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Mendelian Randomization Analysis

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