title: Prioritising new antihypertensive drug targets and understanding the genetic basis of disease modulation by antihypertensive drugs using Mendelian randomisation
Creators: name: Le, Nhu Ngoc
Publisher: name: University of Glasgow
Year: 2024

description: Background:
Several critical gaps remain in understanding the detailed effects of antihypertensive drugs on cardiovascular, diabetic, and renal outcomes. This thesis aims to address these gaps using the Mendelian randomisation (MR) framework. The first objective is to systematically evaluate the causal effects of genetically predicted systolic blood pressure (SBP) and various antihypertensive drug classes on a range of cardiovascular, diabetic, and renal outcomes. The second objective is to discover if any detected associations are mediated through the transcriptions of genes encoding proteins targeted by the corresponding antihypertensive drug classes.

Methods:
Both established and newly developed drugs, as well as first-line and non-first-line therapies, were included in this study. Two-sample MR was conducted to investigate the causal effects of genetically proxied SBP reduction and antihypertensive drug classes on seven outcomes: coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), ischemic stroke, chronic kidney disease (CKD), and type 2 diabetes (T2D). Summary statistics were obtained from the largest European ancestry genome-wide association studies (GWAS). Sensitivity analyses (MR Egger, weighted median, simple median, negative control outcome) were performed to evaluate the robustness of the MR findings to potential biases. Summary-based MR (SMR), which integrates data from GWAS and eQTL studies, was performed to investigate if the detected drug-outcome associations were mediated through gene transcription. eQTL data were obtained from GTEx v8 for the main analysis, and from the eQTLGen consortium for the sensitivity analysis. To evaluate whether the observed associations were due to a shared causal variant or linkage scenario, the Heterogeneity in Dependent Instruments (HEIDI) test and colocalisation were performed.

Results:
Genetically proxied SBP reduction was associated with a lower risk of all the outcomes. The observed associations of genetically proxied calcium channel blockers, angiotensin-converting enzyme inhibitors, and beta-blockers with cardiovascular diseases were consistent with the findings from previous randomised controlled trials and observational studies. New associations were observed between the following genetically predicted drug classes and the outcomes: angiotensinogen inhibition and a decreased risk of CAD and ischemic stroke; loop diuretic and a decreased risk of CAD; endothelin receptor antagonists and a decreased risk of CAD and ischemic stroke; PDE5 inhibition and a lower risk of CAD, ischemic stroke, and CKD; sGC stimulation and a decreased risk of CAD, MI, and CKD. SMR analysis found significant associations of genetically increased GUCY1A3 expression in tibial artery with lower SBP and with a reduced risk of CAD (pSMR = 1.74×10⁻⁰⁶; pHEIDI = 0.664, H₄ = 0.99), genetically increased PDE5A expression in aorta with higher SBP and with increased risk of CAD (pSMR = 9.12×10⁻⁰⁶, pHEIDI = 0.338, H₄ = 0.48), genetically increased KCNH2 expression in the brain cerebellum was associated with higher SBP and increased risk of AF (pSMR = 6.02×10⁻⁰⁵, pHEIDI = 0.195, H₃ = 0.99).

Discussion:
The consistency of MR estimates across various methods enhances confidence in the results, contributing to the credibility of genetic approaches in pharmacological research. The SMR method applied in the studies to identify if the effect of a genetic variant on a phenotype is mediated by gene expression provides insights into the biological pathways involved in drug actions and potential targets for therapeutic interventions. Causal variants in GUCY1A3 and PDE5A suggest that these genes play a central role in BP regulation across different tissues, indicating that modulation of these genes’ expression could influence cardiovascular outcomes.

Conclusion:
This thesis makes a significant contribution to the field by offering new insights and perspectives through the use of Mendelian randomisation and the integration of GWAS and eQTL data using the SMR method providing a more detailed understanding of the genetic mechanisms underlying BP regulation and cardiovascular outcomes. The results from this thesis support the need for further research to validate and functionally characterise these findings followed by clinical effectiveness trials for clinical translation.