Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease
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BiBTeXCONTEXT: 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.
PubMed ID: 31169883
Projects: Genetical Statistics and Systems Biology, LIFE Adult, LIFE Heart
Publication type: Not specified
Journal: Journal of Clinical Endocrinology & Metabolism
Human Diseases: Coronary artery disease
Citation:
Date Published: 6th Jun 2019
Registered Mode: by PubMed ID
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Created: 24th May 2019 at 10:10
Last updated: 7th Dec 2021 at 17:58
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Public web page: http://www.imise.uni-leipzig.de/en/Groups/GenStat/
Start date: 1st Jan 2013
Supplement Data for Publication including Supplement Material & Results (eQTL annotation, Mendelian Randomization (MR), further significant loci), Figures (correlation plot of steroid hormones, scatter plot of genetic effect sizes, regional association plots, scatter plots of MR) and Tables (Correlations, GWAS summary statistics, interaction tests, MR results)
Submitter: René Hänsel
Investigation: OMICS Investigations
Resources: Summary Statistics, Supplement Data
Study type: Genetic study
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Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
https://orcid.org/0000-0001-8344-0658
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Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig
Prof. Dr. Markus Löffler Universität Leipzig Institut für Medizinische Informatik, Statistik und Epidemiologie Härtelstraße 16-18 04107 Leipzig
Projects: LIFE Heart, LIFE - Leipzig Research Center for Civilization Diseases, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles, e:Med, Genetical Statistics and Systems Biology, Task Force COVID-19 Leipzig, NFDI4Health
Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
Markus Scholz Scientific Speaker Institution Institut für Medizinische Informatik, Statistik und Epidemiologie Universität Leipzig Härtelstraße 16-18 04107 Leipzig
Projects: LIFE Heart, LIFE - Leipzig Research Center for Civilization Diseases, LIFE HNC - Head and Neck Cancer Group, SepNet - German Competence Network Sepsis, GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer, LIFE Child, GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer, LIFE Adult
Web page: https://www.uniklinikum-leipzig.de/einrichtungen/life
Taxonomy URI: http://purl.obolibrary.org/obo/DOID_3393
Synonyms: Coronary disease, coronary heart disease, CHD (coronary heart disease), coronary arteriosclerosis
Definitions: Xref MGI., An artery disease that is characterized by plaque building up along the inner walls of the arteries of the heart resulting in a narrowing of the arteries and a reduced blood supply to the cardiac muscles.
