Genetically Determined Blood Pressure, Antihypertensive Drugs, and Genes with Clinical Outcome after Ischemic Stroke: Evidence from Mendelian Randomization

Background Observational studies suggest a robust association between blood pressure (BP) and functional outcomes in ischemic stroke patients. We sought to identify novel associations of the genetic basis of 3-month functional outcome after ischemic stroke based on a Mendelian randomization (MR) framework. Methods We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drugs from genome-wide association studies (GWAS) on 757,601 individuals. The primary outcome was 3- month favorable functional outcome defined as modified Rankin Scale (mRS) of 0-2. The secondary outcome was excellent 90-day outcome defined as mRS 0-1. The Cochran’s Q statistic in Inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-SNP-out analysis, MR-Pleiotropy Residual Sum and Outlier methods were adopted as sensitivity analyses. To validate our primary results, we performed independent repeat analyses and Bi-directional MR analyses. Results Genetic predisposition to higher systolic and diastolic BP was associated with a lower probability of 3-month excellent functional outcome after ischemic stroke in univariable IVW MR analysis (OR=1.29, 95%CI 1.05-1.59, p =0.014; OR=1.27, 95%CI 1.07-1.51, p =0.006, respectively). Pulse pressure was associated with both excellent and favorable functional outcome (OR=1.05, 95%CI 1.02-1.08, p =0.002; OR=1.04, 95%CI 1.01-1.07, p =0.009, respectively). Angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker (CCB), were significantly associated with improved favorable functional outcome (OR=0.76, 95%CI 0.62-0.94, p =0.009; OR=0.89, 95%CI 0.83-0.97, p =0.005). Proxies for β-blockers, angiotensin receptor blocker (ARB) and thiazides failed to show associations with functional outcome ( p >0.05). Conclusion We provide evidence for a potential association of genetic predisposition to higher BP with higher risk of 3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive drugs for improving functional outcome in ischemic stroke.