Genetically Determined Blood Pressure, Antihypertensive Medications, and Risk of Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study

Abstract

ABSTRACT<break><break>Background: Observational studies suggest that different classes of antihypertensive drugs may have different effects on the occurrence of intracranial aneurysm(IA) and subarachnoid hemorrhage(SAH). However, the reported effects in previous studies are inconsistent, and randomised data are absent. We performed a two-sample Mendelian randomization(MR) analysis to study the causal effects of genetically determined blood pressure(BP) and genetic proxies for antihypertensive drug classes on the risk of IA and SAH.<break><break>Methods: Genetic instruments and outcome data were obtained from independent genome-wide association studies(GWAS) or published data, which were exclusively restricted to european ancestry. Causal relationships were identified using inverse-variance weighted MR analyses and a series of statistical sensitivity analyses. The Finngen consortium was used for repeated analysis to verify results obtained from above GWAS.<break><break>Results: Two-sample MR analysis showed that genetically determined Systolic BP, Dystolic BP and Pulse Pressure were related to higher risk of IA and SAH. Based on indentified single nucleotide polymorphisms (SNPs) that influence the effect of calcium channel blockers (CCB, 43 SNPs), beta-blockers (BB, 30 SNPs), angiotensin-converting enzyme inhibitors (ACEI, 16 SNPs), angiotensin receptor blockers (ARB, 11 SNPs), and thiazides (5 SNPs), genetically determined effect of CCBs was associated with higher risk of IA (OR, 1.08 [95%CI, 1.04-1.12], P=1.2110-5) and SAH (OR, 1.07 [95%CI, 1.02-1.12], P=2.0510-3). No associations were found between other antihypertensive drugs and risk of IA or SAH. The effect of CCBs on SAH was confirmed in Finngen consortium samples(OR, 1.04 [95%CI, 1.00-1.08], P=0.042).<break><break>Conclusion: This MR analysis supports the protection effect of hypertension control on the occurrence of intracranial aneurysm and subarachnoid hemorrhage . However, genetic proxies for calcium channel blockers were associated with increased risk of intracranial aneurysm and subarachnoid hemorrhage. Further studies are required to confirm these findings and investigate the underlying mechanisms.