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

Abhiram S. Rao, Daniel Lindholm, Manuel A. Rivas, Joshua W. Knowles, Stephen B. Montgomery, Erik Ingelsson
doi: https://doi.org/10.1101/210302
Abhiram S. Rao
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Daniel Lindholm
2Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden (DL)
3Uppsala Clinical Research Center, Uppsala, Sweden
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Manuel A. Rivas
4Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
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Joshua W. Knowles
5Division of Cardiology, Department of Medicine, Stanford University, Stanford, CA 94305, USA
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Stephen B. Montgomery
6Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
7Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Erik Ingelsson
8Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: eriking@stanford.edu
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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.

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Posted October 27, 2017.
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Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke
Abhiram S. Rao, Daniel Lindholm, Manuel A. Rivas, Joshua W. Knowles, Stephen B. Montgomery, Erik Ingelsson
bioRxiv 210302; doi: https://doi.org/10.1101/210302
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Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke
Abhiram S. Rao, Daniel Lindholm, Manuel A. Rivas, Joshua W. Knowles, Stephen B. Montgomery, Erik Ingelsson
bioRxiv 210302; doi: https://doi.org/10.1101/210302

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