Genetically predicted androgenic profiles and adverse cardiac markers: a sex-specific Mendelian randomization study

Abstract

Aims: Observational evidence suggests associations between sex hormone levels and heart failure (HF). We used sex-specific genetic variants associated with androgenic sex hormone profiles to investigate the causal relevance of androgenic sex hormone profiles on cardiac structure and function and HF using Mendelian randomization (MR).

Methods and results: Sex-specific uncorrelated genome-wide significant (P < 5 × 10^-8 ) variants predicting sex hormone-binding globulin (SHBG), total testosterone, and bioavailable testosterone were extracted from summary statistics of genome-wide association study (GWAS) on 425 097 participants in the UK Biobank. Sex-specific gene-outcome association estimates were computed for left ventricular ejection fraction (LVEF), left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively), left ventricular stroke volume (LVSV), cardiac index, and cardiac output in 11 528 female and 14 356 male UK Biobank Imaging Study participants and for incident or prevalent HF in an external cohort of 47 309 cases and 930 014 controls. Inverse-variance weighted MR was the primary analysis method. In females, higher genetically predicted bioavailable testosterone was associated with lower LVEDV [β per nmol/L = -0.11 (-0.19 to -0.03), P = 0.006], lower LVESV [β = -0.09 (-0.17 to -0.01), P = 0.022], lower LVSV [β = -0.11 (-0.18 to -0.03), P = 0.005], lower cardiac output [β = -0.08 (-0.16 to 0.00), P = 0.046], and lower cardiac index [β = -0.08 (-0.16 to -0.01), P = 0.034] and a higher risk of HF [odds ratio 1.10 (1.01-1.19), P = 0.026] on external validation analysis in larger scale, sex-adjusted GWAS data. Higher genetically predicted SHBG was associated with higher LVEDV [β per nmol/L = 0.17 (0.08-0.25), P = 2 × 10^-4 ], higher LVESV [β = 0.13 (0.05-0.22), P = 0.003], and higher LVSV [β = 0.18 (0.08-0.28), P = 2 × 10^-4 ]. In males, higher genetically predicted total and bioavailable testosterone was associated with lower LVESV [β = -0.07 (-0.12 to -0.02), P = 0.007] and LVEF [β = -0.11 (-0.18 to -0.04), P = 0.003], respectively.

Conclusions: This study supports a causal effect of pro-androgenic sex hormone profiles in females on adverse markers of left ventricular structure and function typically associated with HF with preserved ejection fraction and with HF. There was weaker evidence of association in males.

Keywords: CMR; Heart failure; Mendelian randomization; SHBG; Sex hormones; Testosterone.