Endogenous DHEAS Is Causally Linked With Lumbar Spine Bone Mineral Density and Forearm Fractures in Women.

CONTEXT: A recent pooled analysis of four clinical trials demonstrated that treatment with dehydroepiandrosterone (DHEA) increases lumbar spine bone mineral density (LS-BMD) in women. The causal effect of endogenous adrenal-derived DHEA sulphate (DHEAS) on LS-BMD and fracture risk in women is unknown. OBJECTIVE: To determine whether circulating DHEAS is causally associated with LS-BMD and fracture risk in women. METHODS: A 2-sample Mendelian randomization study using genetic predictors of serum DHEAS derived from the largest available female-specific genome wide association study (GWAS) meta-analysis (n = 8565). Genetic associations with dual-energy X-ray absorptiometry-derived BMD (n = 22 900) were obtained from female-specific GWAS summary statistics available from the Genetic Factors for Osteoporosis consortium while individual-level data of 238 565 women of white ancestry from the UK Biobank were used for associations with fractures (11 564 forearm fractures, 2604 hip fractures) and estimated heel BMD by ultrasound (eBMD). RESULTS: A 1 SD genetically instrumented increase in log serum DHEAS levels was associated with a 0.21 SD increase in LS-BMD (P = 0.01) and a 0.08 SD increase in eBMD (P < 0.001). Genetically predicted DHEAS decreased forearm fracture risk (odds ratio 0.70, 95% CI 0.55-0.88 per SD increase in DHEAS) while no significant causal association with hip fractures was observed. CONCLUSIONS: Genetically predicted serum DHEAS increases LS-BMD and decreases forearm fracture risk in women. Based on the results of the present study and previous randomized controlled trials of DHEA treatment, we propose that both endogenous adrenal-derived DHEA(S) and pharmacological DHEA treatment improve bone health in women.

Association of Genetically Predicted Serum Estradiol With Risk of Thromboembolism in Men: A Mendelian Randomization Study.

CONTEXT: An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men, but a possible causal role of estradiol for risk of thromboembolism in men remains unknown. OBJECTIVE: This work aimed to determine whether endogenous estradiol has a causal role in thromboembolism in men. METHODS: A 2-sample mendelian randomization study using gene-based genetic instruments assessed the association between endogenous estradiol genetically predicted by 22 variants in the aromatase CYP19A1 gene region and the risk of thromboembolism (5815 cases) in 170 593 unrelated men of White ancestry in the UK Biobank. The main outcome measure included thromboembolism based on self-reports, hospital episodes, and death. RESULTS: Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of thromboembolism (odds ratio per SD increase in estradiol 0.74; 95% CI, 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39; 95% CI, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of ischemic stroke (0.68; 95% CI, 0.49-0.95) but not myocardial infarction (0.97; 95% CI, 0.84-1.13). CONCLUSION: Genetically predicted estradiol was inversely associated with the risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by CYP19A1 activity, may contribute to the overall impact of sex steroids on thromboembolism in men.