Sex-Specific Causal Relations between Steroid Hormones and Obesity-A Mendelian Randomization Study.

Janne Pott,Robert Zeidler,Peter Ahnert,Markus Loeffler,Uta Ceglarek,Katrin Horn,Berend Isermann,Markus Scholz,Jürgen Kratzsch,Holger Kirsten

doi:10.3390/metabo11110738

Janne Pott, Robert Zeidler + Show 8 more

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https://doi.org/10.3390/metabo11110738

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Journal: Metabolites	Publication Date: Oct 28, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Leipzig University, University Hospital Leipzig

Abstract

Steroid hormones act as important regulators of physiological processes including gene expression. They provide possible mechanistic explanations of observed sex-dimorphisms in obesity and coronary artery disease (CAD). Here, we aim to unravel causal relationships between steroid hormones, obesity, and CAD in a sex-specific manner. In genome-wide meta-analyses of four steroid hormone levels and one hormone ratio, we identified 17 genome-wide significant loci of which 11 were novel. Among loci, seven were female-specific, four male-specific, and one was sex-related (stronger effects in females). As one of the loci was the human leukocyte antigen (HLA) region, we analyzed HLA allele counts and found four HLA subtypes linked to 17-OH-progesterone (17-OHP), including HLA-B*14*02. Using Mendelian randomization approaches with four additional hormones as exposure, we detected causal effects of dehydroepiandrosterone sulfate (DHEA-S) and 17-OHP on body mass index (BMI) and waist-to-hip ratio (WHR). The DHEA-S effect was stronger in males. Additionally, we observed the causal effects of testosterone, estradiol, and their ratio on WHR. By mediation analysis, we found a direct sex-unspecific effect of 17-OHP on CAD while the other four hormone effects on CAD were mediated by BMI or WHR. In conclusion, we identified the sex-specific causal networks of steroid hormones, obesity-related traits, and CAD.

Highlights

Genome-wide association studies have identified several risk loci in the autosomes [1], but none on chromosome X [2]. This indicates that the observed sex-dimorphism of cardiovascular disease (CVD) risk is not primarily driven by gonosomal genetics
We examine if there is an effect of steroid hormones on coronary artery disease (CAD) and test whether it is mediated by obesity
In a sensitivity approach using only strong instruments, i.e., SNPs explaining at least 0.1% of the variance of the considered obesity-related trait, we found no significant causal relationships

Summary

Introduction

We identified the sex-specific causal networks of steroid hormones, obesity-related traits, and CAD. Male sex is an independent risk factor for cardiovascular disease (CVD), but the underlying molecular mechanisms are not fully understood. Genome-wide association studies have identified several risk loci in the autosomes [1], but none on chromosome X [2]. This indicates that the observed sex-dimorphism of CVD risk is not primarily driven by gonosomal genetics. Since steroid metabolism is highly sex-specific, a causal relationship to atherosclerosis risk can be hypothesized, but the underlying molecular mechanisms are only partly understood.

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