Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes. (May 2018)

• Record Type: Journal Article
• Authors: Pott, Janne; Schlegel, Valentin; Teren, Andrej; Horn, Katrin; Kirsten, Holger; Bluecher, Christina; Kratzsch, Juergen; Loeffler, Markus; Thiery, Joachim; Burkhardt, Ralph; Scholz, Markus
• Is Part Of: Circulation. Volume 11:Number 5(2018)
• Publication Date: 2018-05
• Subjects: atherosclerosis -- genome-wide association study; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.117.001992
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. Methods: We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). Results: Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P =1.94×10 −17 ). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P =7.01×10 −9 ) and 7 suggestive hits ( P <1×10 −6 ). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. Conclusions: Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. Clinical Trial Registration: URL:http://www.clinicaltrials.gov . Unique Identifier: NCT00497887. Abstract : Supplemental Digital Content is available in the text.