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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.

SUBMITTER: Rao AS

PROVIDER: S-EPMC6050027 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Large-Scale Phenome-Wide Association Study of <i>PCSK9</i> Variants Demonstrates Protection Against Ischemic Stroke.

Rao Abhiram S AS Lindholm Daniel D Rivas Manuel A MA Knowles Joshua W JW Montgomery Stephen B SB Ingelsson Erik E

Circulation. Genomic and precision medicine 20180701 7

<h4>Background</h4><i>PCSK9</i> 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.<h4>Methods</h4>We tested the association of the <i>PCSK9</i> missense variant rs1 ...[more]

PMID: 29997226

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Project description:BackgroundElectronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administration raise questions about the consistency and reproducibility of EHR-based multimorbidity research.MethodsUtilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combing data from multiple sources for online multimorbidity analysis.FindingsAnalyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies ( Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest a similar structure of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights.InterpretationOur findings demonstrate the robustness of large-scale EHR data for studying complex disease interactions. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared etiology of diseases. The consistent core-periphery network structure offers a strategic approach to analyze disease clusters. This work also sets the stage for advanced disease modeling, with implications for precision medicine.FundingVUMC Biostatistics Development Award, UL1 TR002243, R21DK127075, R01HL140074, P50GM115305, R01CA227481.

Dataset Information

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

Publications

Large-Scale Phenome-Wide Association Study of <i>PCSK9</i> Variants Demonstrates Protection Against Ischemic Stroke.

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