Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke

Abstract

Background: PCSK9 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 PCSK9 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 PCSK9 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; P=2.32×10^-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10^-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10^-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10^-7). 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 PCSK9 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 PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 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.

Keywords: atrial fibrillation; diabetes mellitus, type 2; heart failure; humans; stroke.

Figure 1

Summary of associations in the hypothesis-directed phenotype set. Forest plot estimates are based on the discovery analysis, and all p-values reported are unadjusted. There was no association with a continuous cognitive score assessed by a trail making test (not shown here, beta = 0.03 ± 0.19, p = 0.86). The association with T2D is unadjusted for lipid medication; adjustment was performed in a subsequent re-analysis.

Figure 2

Summary of significant associations in the hypothesis-generating phenotype set. Forest plot estimates are based on the discovery analysis, and all p-values reported are unadjusted. PCI – percutaneous coronary interventions.

Figure 3

TreeWAS association results for rs11591147 (T) across the phenome. Significant associations are labeled.