Genetic Association Study of Eight Steroid Hormones and Implications for Sexual Dimorphism of Coronary Artery Disease

Abstract

Context Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. Objective Our main objective was to identify genetic loci influencing steroid hormone levels. As a secondary aim, we searched for causal effects of steroid hormones on CAD. Design We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, dehydroepiandrosterone sulfate (DHEAS), estradiol, and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, maximum n = 7667), and progesterone, 17-hydroxyprogesterone, androstenedione, and aldosterone in LIFE-Heart only (maximum n = 2070). All genome-wide significant loci were tested for sex interactions. Furthermore, we tested whether previously reported CAD single-nucleotide polymorphisms were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian randomization (MR) approaches. Results We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEAS, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism, that is, CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, for example, to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone, and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. Conclusion Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sexual dimorphism in other complex diseases.

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

“…We tested whether genetically-elevated cortisol is causally associated with cortisol-related outcomes selected from the features of Cushing’s syndrome – a rare condition caused by tumours secreting ACTH or cortisol - that are highly prevalent in the general population. Consistent with previous reports based on a less refined genetic instrument 13 , 14 we found evidence that cortisol causally increases the risk of heart disease. However, we did not find conclusive evidence that elevated cortisol causes type 2 diabetes, osteoporosis or obesity; given the relatively small variance in cortisol accounted for by the genetic instrument, it is possible that causal associations with additional diseases and traits would be revealed by analysis of larger sample sizes.…”

The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study

“…However, such effect on IHD did not replicate using weighted generalized linear regression or IVW with a correlation matrix for correlated SNPs [60] when applying these SNPs to the CARD IoGRAM [59], CARDIoGRAMplusC4D 1000 Genomesbased GWAS [28], or meta-analysis of UK Biobank and CARDIoGRAMplusC4D [57] (Additional file 1: Table S5). A recent MR study showed genetically predicted cortisol positively associated with IHD [20], based on 2 independent SNPs using one-sample MR among healthy participants and patients with suspected or confirmed IHD, which may be subject to selection bias given prior deaths and/or healthy controls were excluded from the study [61]. No effect on IHD was found when applying these SNPs to the CARDIoGRAMplusC4D 1000 Genomes-based GWAS [28] or UK Biobank GWAS of IHD [29] (Additional file 1: Table S6).…”

“…Particularly for cortisol, a recent MR study suggested genetically predicted cortisol was positively associated with IHD, but its two-sample MR estimates based on limited genetic instruments (n = 3) and its one-sample MR estimates based on three small European cohorts had 95% confidence interval (CI) including the null [19]. Another MR showed genetically predicted cortisol based on two genetic instruments positively associated with IHD using one-sample MR among healthy participants and patients with suspected or confirmed IHD [20]. However, no MR study has explicitly considered the effect of cortisol on IHD using more comprehensive genetic predictors of cortisol, the effect on ischemic stroke, T2DM, and other CVD risk factors or whether cortisol may be a symptom rather than consequence of IHD, ischemic stroke, and T2DM.…”

Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density

“…Previously published genome-wide association studies (GWAS) for estrogen have been performed in cohorts of up to 11,000 individuals, mostly of European descent, both male and female and stratified by sex [11][12][13][14][15] . In addition, a GWAS was recently performed for sex hormone levels in UK biobank (UKB), a study which mainly focused on testosterone 16 .…”

“…When estrogen levels drop during menopause, the cells that synthesize bone (osteoblasts) are unable to effectively produce bone mass 8 . The loss of ovarian estrogens after menopause has been associated with reduced bone mineral density (BMD) and higher risk of osteoporosis 9,10 .Previously published genome-wide association studies (GWAS) for estrogen have been performed in cohorts of up to 11,000 individuals, mostly of European descent, both male and female and stratified by sex [11][12][13][14][15] . In addition, a GWAS was recently performed for sex hormone levels in UK biobank (UKB), a study which mainly focused on testosterone 16 .…”