Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

Abstract

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart 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 well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. 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 low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

Pharmacogenomics of Blood Lipid Regulation

“…This method was first developed by Denny et al in 2010 and its value is now recognized in the context of predicting adverse drug reactions or finding drug repurposing opportunities [66][67][68]. A recent unpublished study tested for the association between the PCSK9 R46L genetic variant and 11 selected phenotypes in a targeted analysis as well as with 278 phenotypes in an exploratory scan using data from the UK Biobank [69]. A protective effect with ischemic stroke (replication OR 0.58 (0.36, 0.89), p=0.02) was detected which is consistent with the known atheroprotective effect of PCSK9 inhibitors and the results from recent clinical trials of evolocumab [50].…”

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease

“…11 More recently, a large case-control study noted an up to 72% reduction (95% CI, 36-88) in CHD among APOB PTV carriers. 9 While informative, these and subsequent similar studies have potential limitations based on the focus of only a single gene, [9][10][11] restriction to specific variants, 10,12 lack of assessment across multiple ancestries, 3,10,13 and case-control rather than prospective study designs, which prevents the follow-up and accurate assessment of how variants in APOB and PCSK9 affect cumulative lifetime LDL cholesterol exposure and the associated effect on CHD risk. 9,11,13 To confirm and extend these prior studies, this study aggregated and harmonized genetic data and clinical phenotypes of more than 200 000 participants from 5 National Heart, Lung, and Blood Institute (NHLBI) prospective cohorts-the ARIC study, the Cardiovascular Risk Development in Young Adults (CARDIA) study, the Cardiovascular Health Study (CHS), the Framingham Offspring Study (FHS-O), and the Multi-Ethnic Study of Atherosclerosis (MESA)-and the UK Biobank to better understand the prevalence of rare PTVs in APOB or PCSK9 and their association with LDL cholesterol and CHD.…”