Association of antihypertensive drug target genes with stroke subtypes: A Mendelian randomization study

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.