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 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, DHEA-S, estradiol and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, max. n=7667), and progesterone, 17-hydroxyprogesterone, androstenedione and aldosterone in LIFE-Heart only (max. n=2070). All genome-wide significant loci were tested for sex interactions. Further, we tested if previously reported CAD SNPs 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, DHEA-S, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism: 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, e.g., 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 sex-dimorphisms in other complex diseases.

LHA-ID: 7WAD3R7GD2-1

PubMed ID: 31169883

DOI: 10.1210/jc.2019-00757

Projects: Genetical Statistics and Systems Biology, LIFE Adult, LIFE Heart

Journal: Journal of Clinical Endocrinology & Metabolism

Human Diseases: Coronary artery disease

Citation:

Date Published: 6th Jun 2019

Authors: Janne Pott, YJ. Bae, K. Horn, A. Teren, Andreas Kühnapfel, H. Kirsten, U. Ceglarek, Markus Löffler, J. Thiery, J. Kratzsch, Markus Scholz

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Pott, J., Bae, Y. J., Horn, K., Teren, A., Kühnapfel, A., Kirsten, H., … Scholz, M. (2019). Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease. The Journal of Clinical Endocrinology & Metabolism. http://doi.org/10.1210/jc.2019-00757
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Created: 24th May 2019 at 10:10

Last updated: 24th May 2019 at 10:13

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