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

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.

Associations Between CYP17A1 and SERPINA6/A1 Polymorphisms, and Cardiometabolic Risk Factors in Black South Africans

“…Instead, a GWAS in European men and women demonstrated that a SNP at SERPINA6/A1, represented by the rs12589136-T allele, was associated with higher circulating cortisol concentrations, while the rs2749527-T and rs11621961-T alleles at the same locus were associated with lower circulating cortisol concentrations (Boonen et al, 2013). Accordingly, a recent European study suggested that these previously identified SERPINA6/A1 SNPs are likely to influence circulating cortisol concentrations by altering hepatic CBG expression (Crawford et al, 2021). Additionally, many cross-sectional studies have suggested that higher circulating cortisol concentrations are associated with an increased risk of developing the metabolic syndrome and its related cardiometabolic risk factors in both African and non-African populations (Walker et al, 2000;Reynolds et al, 2003;Ward et al, 2003).…”

“…Further, in a genome-wide association study (GWAS) in Europeans, inter-individual variation in circulating cortisol concentrations was associated with SNPs at a locus that spans the SERPINA6 and SERPINA1 genes (Bolton et al, 2014). SERPINA6 encodes corticosteroid binding globulin (CBG), the primary glucocorticoid-binding protein in circulation, while SERPINA1 encodes alpha-1 antitrypsin, which is involved in the regulation of the binding and release of glucocorticoids from CBG (Henley and Lightman, 2011;Crawford et al, 2021). However, associations between SNPs at SERPINA6/A1 and the metabolic syndrome and related cardiometabolic risk factors remain to be investigated.…”

Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?

“…Consequently, in line with the free hormone hypothesis, this means that only between 2 and 10% of glucocorticoids are able to diffuse into tissues and cells and exert biological activity. Recent genome-wide association studies have demonstrated the importance of CBG in regulating circulating levels, with genetic variation in the SERPINA6/1 locus influencing hepatic SERPINA6 expression associated with morning plasma cortisol [35,124]. Unsurprisingly, given the role of glucocorticoids in numerous physiological settings, CBG has been postulated to play a significant role in glucocorticoid action in several pathological conditions.…”

“…Together, the evidence for an association between increased exposure to glucocorticoids and increased CVD risk is clear, yet the question of causality remains. Using Mendelian randomisation and data collected across 17 studies of European ancestry, a recent study tested whether genetically elevated cortisol in the general population is causally associated with a number of cardiovascular risk factors [ 35 ]. Importantly, the authors demonstrate that increased cortisol causally increases the risk of ischaemic heart disease and myocardial infarction.…”

Cystatin C is glucocorticoid-responsive, directs recruitment of Trem2+ macrophages and predicts failure of cancer immunotherapy

“…This is not without consequence -alterations in cortisol production (and chronic GC treatment 36 ) are associated with the onset of metabolic syndrome 37,38 , a cluster of interrelated conditions including hypertension, insulin resistance, dyslipidemia and obesity, which is in turn associated with increased risk of cardiovascular disease and type 2 diabetes 39 . Twin studies have demonstrated relatively high heritability in plasma cortisol 40 , suggesting that inter-individual variability in endogenous cortisol production may have a significant genetic component, which has remained largely unexplained by GWAS to date 41 .…”