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

Wilson James F.; Price Jackie; Hayward Caroline; Eriksson Johan; Walker Brian R.; on behalf of the CORtisol NETwork (CORNET) consortium; Mahajan Anubha; Joshi Peter K.; Timpson Nicolas J.; Friedrich Nele; Crawford Andrew A.; Morris Andrew P.; Barnes Catriona L. K.; Völzke Henry; Lahti Jari; Bankier Sean; Bjorkegren Johan L. M.; Neumann Alexander; Jarvelin Marjo-Riitta; Tiemeier Henning; Pietzner Maik; Karhunen Ville; Ruusalepp Arno; Pennell Craig E.; McLachlan Stela; Clark David W.; Michoel Tom; van der Harst Pim; Bakker Stephan J. L.; Mangino Massimo; Rudan Igor; Nethander Maria; Ermel Raili; Spector Tim; Smith George Davey; Campbell Harry; Ohlsson Claes; Altmaier Elisabeth; Sukhavasi Katyayani; Wang Carol A.; Gieger Christian
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

Wilson James F.
Price Jackie
Hayward Caroline
Eriksson Johan
Walker Brian R.; on behalf of the CORtisol NETwork (CORNET) consortium
Mahajan Anubha
Joshi Peter K.
Timpson Nicolas J.
Friedrich Nele
Crawford Andrew A.
Morris Andrew P.
Barnes Catriona L. K.
Völzke Henry
Lahti Jari
Bankier Sean
Bjorkegren Johan L. M.
Neumann Alexander
Jarvelin Marjo-Riitta
Tiemeier Henning
Pietzner Maik
Karhunen Ville
Ruusalepp Arno
Pennell Craig E.
McLachlan Stela
Clark David W.
Michoel Tom
van der Harst Pim
Bakker Stephan J. L.
Mangino Massimo
Rudan Igor
Nethander Maria
Ermel Raili
Spector Tim
Smith George Davey
Campbell Harry
Ohlsson Claes
Altmaier Elisabeth
Sukhavasi Katyayani
Wang Carol A.
Gieger Christian
Katso/Avaa
Lataukset: 

SPRINGERNATURE
doi:10.1038/s10038-020-00895-6
URI
https://doi.org/10.1038/s10038-020-00895-6
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042825658
Tiivistelmä

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 similar to 2.2 M to similar 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 alpha 1-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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