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.
Adrenal Cortex Hormones
/ blood
Adult
Biological Specimen Banks
Cardiovascular Diseases
/ blood
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Liver
/ metabolism
Male
Mendelian Randomization Analysis
Middle Aged
Myocardial Infarction
/ blood
Polymorphism, Single Nucleotide
/ genetics
Quantitative Trait Loci
/ genetics
Transcortin
/ genetics
United Kingdom
alpha 1-Antitrypsin
/ genetics
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
03
11
2020
accepted:
14
12
2020
revised:
14
12
2020
pubmed:
21
1
2021
medline:
3
9
2021
entrez:
20
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33469137
doi: 10.1038/s10038-020-00895-6
pii: 10.1038/s10038-020-00895-6
pmc: PMC8144017
mid: EMS114696
doi:
Substances chimiques
Adrenal Cortex Hormones
0
SERPINA1 protein, human
0
SERPINA6 protein, human
0
alpha 1-Antitrypsin
0
Transcortin
9010-38-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
625-636Subventions
Organisme : Chief Scientist Office
ID : CZB/4/733
Pays : United Kingdom
Organisme : British Heart Foundation (BHF)
ID : RG/11/4/28734
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : 107049/Z/15/Z
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202802/Z/16/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/11/4/28734
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098017
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : Wellcome Trust
ID : 090532
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107049
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 064890
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : RCUK | Medical Research Council (MRC)
ID : 1938124
Investigateurs
Dan Mellström
(D)
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