Large-Scale Phenome-Wide Association Study of Variants Demonstrates Protection Against Ischemic Stroke.

BACKGROUND: inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes.

METHODS: We tested the association of the missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of inhibition with higher power at a finer resolution.

RESULTS: The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; =2.32×10), coronary heart disease (odds ratio, 0.73±0.09; =1.05×10), and ischemic stroke (odds ratio, 0.61±0.18; =2.40×10) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; =1.98×10). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct inhibition; off-target effects cannot be predicted using this approach.

CONCLUSIONS: This result represents the first genetic evidence in a large cohort for the protective effect of inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.