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Published on: March 2, 2011
Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network
Yunxia Li1, Shucheng Si1, Lei Hou1
1Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
Insights
Sex hormone-binding globulin (SHBG) and testosterone (T) show a causal link to reduced coronary heart disease (CHD) risk. Network analysis reveals a bidirectional relationship, suggesting T may mediate SHBG
Area of Science:
- Endocrinology and Metabolism
- Cardiovascular Research
- Genetic Epidemiology
Background:
- Observational studies suggest links between sex hormone-binding globulin (SHBG), testosterone (T), and cardiovascular diseases (CVD), but causality remains debated.
- Investigating the causal relationship between SHBG, T, and coronary heart disease (CHD) is crucial for understanding CVD etiology.
Purpose of the Study:
- To explore the causal effects of SHBG and total testosterone (TT) on the risk of coronary heart disease (CHD).
- To elucidate the potential mediating roles of SHBG and TT in the pathway to CHD.
Main Methods:
- Employed univariable, multivariable, and network Mendelian randomization (MR) analyses.
- Utilized UK Biobank data for SHBG and TT genetic variants (approx. 180,000 men) and CARDIoGRAMplusC4D GWAS data for CHD cases and controls (approx. 184,000 individuals).
- Inverse variance weighted (IVW) MR served as the primary analysis, with sensitivity analyses to confirm robustness.
Main Results:
- Univariable MR indicated a decreased risk of CHD with increased SHBG (14%) and TT (8%).
- Multivariable MR suggested no direct causal effect of SHBG or TT on CHD.
- Network MR identified a bidirectional causal relationship, with TT potentially mediating 93% of SHBG's effect and SHBG mediating 67% of TT's effect on CHD.
Conclusions:
- Genetically predicted SHBG and TT are negatively correlated with CHD risk, supporting a causal link.
- A bidirectional causal effect exists between SHBG and TT in relation to CHD.
- Further research is needed to clarify downstream effects and molecular pathways for potential therapeutic strategies in CHD prevention.
Background:
Although observational studies have shown an association between sex hormone-binding globulin (SHBG), testosterone (T) and cardiovascular diseases (CVD), controversy remains. In this study, we aim to explore the causal effects of SHBG and T on Coronary heart disease (CHD).
Methods:
We used univariable, network and multivariable mendelian randomization (MR) analysis to investigate the causal effect of SHBG and T on CHD. We performed inverse variance weighted (IVW) MR as the primary analysis, with the robustness of this approach further tested by other methods in sensitivity analysis. The SHBG and T were collected from the UK Biobank data, about 180,000 men aged 40 to 69 years. CHD was collected from CARDIoGRAMplusC4D 1000 Genomes-based GWAS, which was a meta-analysis including 48 studies and involving 60,801 CHD cases and 123,504 controls.
Results:
Using univariable MR-IVW, the results suggested that a one standard deviation (SD) increase in SHBG, the risk of CHD decreased by approximately 14% (OR (95% CI): 0.86(0.76,0.97)), and that a SD increase in total testosterone (TT), the risk also decreased, approximately 8% (OR (95% CI): 0.92(0.85,0.99)). Multivariable MR showed that both SHBG and TT had no direct causal effect with CHD (a SD increase in SHBG: OR (95% CI):0.75(0.57,1.00), P = 0.053; a SD increase in TT: OR (95% CI): 1.05(0.90,1.22), P = 0.53). In the network MR analysis, the results suggested that TT might act as mediator in the causal pathway from SHBG to CHD and account for 93% of the total effect of SHBG on CHD, and that SHBG might be a mediator in the causal pathway from TT to CHD and account for 67% of the total effect of TT on CHD.
Conclusions:
Genetically predicted SHBG and TT were negatively correlated with CHD in both univariable and network MR, which may provide a causal explanation behind the observed conclusion. In addition, TT and SHBG had a bidirectional causal effect. Further work is required to disentangle the downstream effects of SHBG/TT on CHD and the molecular pathways involved, as the simultaneous regulation of SHBG and TT may make it a viable strategy for the prevention or treatment of CHD.
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