Genetic variation supports a causal role for valproate in prevention of ischemic stroke

Abstract Background and ObjectivesValproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke risk in the UK Biobank (UKB). MethodsUsing independent genome-wide association data of seizure response after valproate intake from the EpiPGX consortium, a genetic score for valproate response was derived. Valproate users were identified from UKB baseline and primary care data, and the association of the genetic score with incident and recurrent ischemic stroke was tested in Cox proportional hazard models. ResultsAmong 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. A higher genetic score was associated with an increased effect of valproate dose on serum valproate levels (+0.48 μg/ml per 100mg/day per one SD, 95%CI[0.28, 0.68]). After adjusting for age and sex, a higher genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). In the 194 valproate users with prevalent stroke at baseline, a higher genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal contribution of pleiotropic effects from included genetic variants. DiscussionAmong valproate users, genetically predicted favorable seizure response to valproate was associated with higher serum valproate levels and reduced ischemic stroke risk, providing causal support for valproate utility in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials are warranted to identify populations that may benefit most from valproate for stroke prevention.