Identification of novel targets for therapy with PCSK9: From LDL lowering to decreased inflammation and coagulation

Abstract

Venous thrombosis is a potentially lethal disease that occurs in about 1-2/1000 people yearly and recurs in about 20-25% of patients within 5-10 years. New insights are linking thrombosis with inflammation, a concept called immunothrombosis. Recent work has shown that inflammatory response leads to increased levels of coagulation, dyslipidemia, atherosclerosis and thrombosis. Currently, it has been shown that some statins (most notably, rosuvastatin) decrease venous thrombosis risk possibly because rosuvastatin has anti-inflammatory properties apart from LDL lowering. Point mutations in the PCSK9 gene lead to strong LDL reductions (0.28 to 0.54 mmol/L) and are also associated with a 47% reduction in risk of cardiovascular disease in carriers versus noncarriers. Interestingly, this risk reduction is considerably more pronounced than that expected from statin trials, where a similar reduction in LDL would have caused an approximately 9-15% reduction in cardiovascular risk. Why this discrepancy between predicted and observed risk associated with PCSK9 polymorphisms is as yet unknown. It is possible that PCSK9 gene polymorphisms reduce the risk of cardiovascular disease by additional mechanisms besides the LDL-lowering effect. Although experimental data suggest that the suppression of PCSK9 has anti-inflammatory effects, no lipid independent effects of PCSK9 have been demonstrated in clinical studies so far.We hypothesize that PCSK9 variants may be associated with pleiotropic anti-inflammatory properties. Furthermore, these properties may influence the risk of venous thrombosis and PCSK9 inhibitors may be investigated as novel therapies to prevent venous thrombosis.Therefore, our main objective is to identify anti-inflammatory or anticoagulant pleiotropic properties of PCSK9 polymorfism R46L that may lead to novel treatment targets to prevent thrombosis without increasing the bleeding risk.In two large clinical studies genotyping of PCSK946L(rs11591147) will be tested. We will perform Mendelian randomization studies in the existing data- and biobanks of these studies, where DNA (for PCSK9 genotyping), clinical information, serum, plasma, and disease outcome data are all already available. NEO cohort study of obese patients (6606 patients) will be the hypothesis generating study and MEGA case-control study of patients with thrombosis (5000 patients and 5000 controls) will be the etiological study. Genotyping for PCSK9 R46L (rs11591147) will be carried out using real time PCR.In the advent of PCSK9 inhibitor development, results from this proposal could be relevant as a serendipity's gift - meaning that a powerful anti-inflammatory or anticoagulant action responsible for benefit in venous thrombosis risk reduction by targeting PCSK9 could be identified.