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Published on: August 18, 2015
Association of antihypertensive drug target genes with stroke subtypes: A Mendelian randomization study
He Zheng1, Wenbin Wang2, Weida Qiu2
1School of Medicine, South China University of Technology, Guangzhou, China; Department of Cardiology, Hypertension Research Laboratory, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Insights
Antihypertensive medications (AHM) may reduce stroke risk by altering KCNJ11 and ADRB1 gene expression. NHLRC2 is identified as a potential therapeutic target for small vessel stroke (SVS).
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Stroke Research
Background:
- Antihypertensive medications (AHM) impact stroke risk, but the specific genetic targets and mechanisms remain unclear.
- Understanding gene-drug interactions is crucial for personalized stroke prevention strategies.
Purpose of the Study:
- To investigate the impact of AHM on stroke subtypes by examining target gene expression.
- To identify specific genes and pathways through which AHM influence stroke risk.
Main Methods:
- Utilized genetic instruments and expression quantitative trait loci (eQTLs) in blood to proxy AHM effects on gene expression.
- Employed sensitivity analyses including colocalization and pleiotropy checks to validate findings.
Main Results:
- Decreased KCNJ11 gene expression correlated with reduced systolic blood pressure (SBP) and lower risk of any stroke and ischemic stroke.
- ADRB1 gene expression was negatively associated with small vessel stroke (SVS) risk.
- Evidence supported shared causal variants for KCNJ11 and ADRB1 in stroke subtypes; NHLRC2 also linked to SVS risk.
Conclusions:
- KCNJ11 and ADRB1 gene expression changes, potentially mediated by AHM, may lower stroke risk.
- NHLRC2 emerges as a potential therapeutic target for small vessel stroke.
Objective:
Epidemiological and genetic studies have elucidated the effect of antihypertensive medication (AHM) on stroke subtypes varying upon drug classes, but which drug target genes, how, and where mediated this association remains unknown. We aimed to investigate the impact of AHM on stroke subtypes.
Methods:
Genetic instruments for the expression of AHM target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure (SBP) to proxy for the effect of AHM. Sensitivity analysis, including reverse causality detection, horizontal pleiotropy, phenotype scanning, tissue enrichment analyses, Bayesian colocalization, and linkage disequilibrium check, were utilized to validate our findings.
Results:
A 1-standard deviation (SD) decrease of KCNJ11 gene expression (acting on arteriolar smooth muscle) was associated with a decrease of 2.19 (95 % confidence interval (CI), 1.67-2.71) mmHg of SBP, and a decreased risk of stroke subtypes (Any stroke: odds ratio (OR): 0.80, 95 % CI: 0.70-0.90; Ischemic stroke: OR, 0.79; 95 % CI, 0.69-0.90), respectively. Similarly, a negative association was found between the gene expression of ADRB1 and the risk of small vessel stroke (SVS) (OR, 0.61; 95 % CI, 0.49-0.75). Colocalization supported the probability of shared causal variants for the KCNJ11 and ADRB1 genes in different stroke subtypes. NHLRC2, the nearby gene of ADRB1, was also associated with a higher risk of SVS.
Conclusion:
Our study implies that changes in expression of KCNJ11 and ADRB1 mediated possibly via AHM may decrease stroke subtypes' risk and NHLRC2 is a potential therapy target gene of SVS.
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