DOI: 10.1097/rd9.0000000000000170 ISSN: 2096-2924

Genetic evidence for a protective effect of female testosterone and cardiovascular disease in women: A Mendelian randomization study with gut microbiome mediation analysis

Yi-Jing Chen, Jie-Long Huang, Ren-Ke He, Jian-Ping Zhou, Zeng-Nan Mo, Jun Li, Zhong-Zhong Chen
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Objective:

Testosterone influences urogenital development during embryogenesis and metabolic–cardiovascular homeostasis in adult women. Observational links between testosterone abnormalities and cardiovascular disease (CVD) are inconclusive due to confounding and reverse causation. We aimed to assess the genetically predicted associations of endogenous sex hormones with CVD risk in women and to explore potential gut microbiota involvement.

Methods:

Two-sample Mendelian randomization (MR) was conducted to assess associations of bioavailable testosterone (BioT), total testosterone (TotalT), free testosterone (FreeT), and estradiol levels with seven prespecified cardiovascular outcomes. Instruments were derived from published genome-wide association studies (GWASs) in women of European ancestry (sample sizes: 158,089–188,507). Inverse-variance weighted (IVW) MR was the primary approach, complemented by MR-Egger, weighted median, and sensitivity analyses. Two-step mediation MR and multivariable MR (MVMR) were performed using GWAS data on 119 gut microbial genera to explore microbiome-related pathways. Genetic correlations were estimated using linkage disequilibrium score regression (LDSC).

Results:

Higher BioT levels were associated with lower risks of CVD (OR = 0.935, p = 0.034) and coronary heart disease (CHD; OR = 0.886, p = 0.009). TotalT levels were inversely associated with CVD (OR = 0.949, p = 0.039), and FreeT levels with CHD (OR = 0.940, p = 0.043). Mediation MR and MVMR analyses suggested partial microbiome involvement: Haemophilus mediated 10.6% of the TotalT–CVD association, and Holdemanella mediated 10.1% of the BioT–CVD association. LDSC revealed significant negative genetic correlations of BioT levels with CHD and CVD (all p < 1 × 10 -5 ) and of TotalT and FreeT levels with secondary right heart disease ( p < 0.05). Estradiol levels were not significantly associated with the studied cardiovascular outcomes.

Conclusion:

Genetically predicted testosterone-related traits showed inverse associations with CVD risk in women and evidence of shared genetic architecture with several cardiovascular outcomes. Exploratory mediation analyses suggested that the gut microbiome may partly mediate these relationships, warranting further validation.

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