OR09-04 Common Genetic Variants Associated with SERPINA6 Expression in Liver Influence Cortisol-Responsive Transcriptional Networks in Human Adipose Tissue

A genome wide meta-analysis by the CORtisol NETwork (CORNET) consortium((1)) has identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14, associated with morning plasma cortisol and predictive of cardiovascular disease (Crawford et al, Unpublished). SERPINA6 encodes Corticosteroid Binding Globulin (CBG), responsible for binding most cortisol in blood and putatively mediating delivery of cortisol to target tissues. We hypothesised that genetic variants in SERPINA6 influence CBG expression in liver and cortisol delivery to extra-hepatic tissues, influencing cortisol-regulated gene expression. The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET)((2)) provides RNA sequencing data in 9 vascular and metabolic tissues from 600 genotyped individuals (mean age 65.8, 70.3% male) undergoing coronary artery bypass grafting. We used STARNET to identify SNPs associated with plasma cortisol at genome wide significance in CORNET as cis-eQTLs for SERPINA6 in liver and as trans-eQTLs for the expression of genes across STARNET tissues. Causal inference methodologies((3)) were then employed for the network reconstruction of these trans-genes and their downstream targets. We identified 21 SNPs that both were associated with cortisol at genome wide significance in CORNET (p ≤ 5x10(-8)) and were cis-eQTLs for SERPINA6 expression in liver (q ≤ 0.05). Moreover, these SNPs were trans-eQTLs for sets of genes in liver, subcutaneous and visceral abdominal adipose tissue, with over-representation of known glucocorticoid-regulated genes in adipose. The highest confidence gene network identified was specific to subcutaneous adipose, with the interferon regulatory trans-gene, IRF2, controlling a putative glucocorticoid-regulated network. Targets in this network include LDB2 and LIPA, both associated with coronary artery disease. We conclude that variants in the SERPINA6/SERPINA1 locus mediate their effect on plasma cortisol through variation in SERPINA6 expression in liver, and in turn affect gene expression in extra-hepatic tissues through modulating cortisol delivery. This supports a dynamic role for CBG in modulating cortisol delivery to tissues. The cortisol-responsive gene networks identified here represent candidate pathways to mediate cardiovascular risk attributable to elevated cortisol. (1) Bolton, et al. (2014) PLOS Genet. 10:e1004474., (2) Franzén et al. (2016). Science 353:827., (3) Wang and Michoel. (2017). PLOS Comput. Biol. 13:e1005703.