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

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.

Genetic variation reveals the influence of steroid hormones on the risk of retinal neurodegenerative diseases

“…Single nucleotide polymorphisms (SNPs) predicting levels of five steroid hormones were obtained from the GWAS by Pott et al. ( 18 ). This GWAS used data from LIFE-Adult (males/females: 863/618) ( 21 ) and LIFE-Heart (males/females: 1357/711) ( 22 ).…”

“…We want to acknowledge the participants and investigators of the GWAS from Pott et al. ( 18 ), FinnGen study ( ), the GWAS from Winkler et al. ( 24 ) and MRC-IEU consortium for sharing the genetic data.…”

“…Pott et al. ( 18 ) also found the sex-specific causal networks of steroid hormones and obesity through MR research. These studies provide additional possibilities for exploring the effects of steroid hormones on disease risk.…”

Assessment of DMFT Indexes, Salivary Flow Rate, Ph, and Detections of S.MUTANS Salivary Levels by a Quantitative Real-Time PCR in Polycystic Ovary Syndrome

“…Estrogen is effective in maintaining the integrity of the oral cavity as well as regulating reproductive functions. 30 High estrogen levels in patients with PCOS affect the vascular permeability of the oral mucosa, which reduces the immune competence of the oral cavity. 31 Zhang et al 32 found that estrogen was present in the cells in the salivary gland ducts and suggested that the salivary glands were one of the estrogen target organs.…”

Roles of sex hormones in mediating the causal effect of vitamin D on osteoporosis: A two-step Mendelian randomization study

“…Data on A4 and T/E2 were obtained from a GWAS ( 17 ) consisting of 3,549 European samples from LIFE-Adult ( 18 ) and LIFE-Heart ( 19 ). This GWAS used liquid chromatography–tandem mass spectrometry to quantitatively determine A4 levels and employed the electrochemiluminescence immunoassay to quantitatively study both T and E2.…”