- 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
- Creator
- Crawford, Andrew A.; Bankier, Sean; Lahti, Jari; Mahajan, Anubha; Mangino, Massimo; Nethander, Maria; Neumann, Alexander; Pietzner, Maik; Sukhavasi, Katyayani; Wang, Carol A.; Bakker, Stephan J. L.; Bjorkegren, Johan L. M.; Altmaier, Elisabeth; Campbell, Harry; Eriksson, Johan; Gieger, Christian; Hayward, Caroline; Jarvelin, Marjo-Riitta; McLachlan, Stela; Morris, Andrew P.; Ohlsson, Claes; Pennell, Craig E.; Price, Jackie; Barnes, Catriona L. K.; Rudan, Igor; Ruusalepp, Arno; Spector, Tim; Tiemeier, Henning; Volzke, Henry; Wilson, James F.; Michoel, Tom; Timpson, Nicolas J.; Smith, George Davey; Walker, Brian R.; Clark, David W.; Ermel, Raili; Friedrich, Nele; van der Harst, Pim; Joshi, Peter K.; Karhunen, Ville
- Relation
- Journal of Human Genetics Vol. 66, Issue 6, p. 625-636
- Publisher Link
- http://dx.doi.org/10.1038/s10038-020-00895-6
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2021
- Description
- 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.
- Subject
- cardiovascular disease; cortisol; SERPINA6/SERPINA1 locus; plasma; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1452113
- Identifier
- uon:44364
- Identifier
- ISSN:1434-5161
- Rights
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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