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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial We don't need clinical trial disclosure ### Funding Statement This study was funded by the Stroke Prevention and Treatment Project of the National Health Commission - Research and Popularization of Appropriate Intervention Technology for the Stroke High Risk Group in China (no. GN-2020R0008), Shanghai Sailing Program (no: 20YF1448000), Naval Medical University Fundamental Research Program (no. 2022QN052) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NONE I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable All data mentioned in the manuscript are true and available * ACEI : angiotensin-converting enzyme inhibitor ARB : angiotensin receptor blocker AIS : acute ischemic stroke OR : odds ratio BP : blood pressure CCB : calcium channel blocker CI : confidence interval DBP : diastolic blood pressure GWAS : genome-wide association studies ICH : intra-cranial hemorrhage LD : linkage disequilibrium IVW : Inverse variance weighted MR : Mendelian randomization mRS : modified Rankin Scale PP : pulse pressure RAS : renin-angiotensin system RCT : randomized controlled trials SD : standard deviation SNP : single nucleotide polymorphisms SBP : systolic blood pressure SVD : small vessel disease