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Journal of Lipid Research, Vol. 51, 140-149, January 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

A new method for measurement of total plasma PCSK9: clinical applications

Geneviève Dubuc^*, Michel Tremblay^*, Guillaume Paré^**, Hélène Jacques^*, Josée Hamelin, Suzanne Benjannet, Lucie Boulet^*, Jacques Genest, Lise Bernier^*, Nabil G. Seidah and Jean Davignon^1,*

^* Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada
^** Harvard Medical School, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA

¹ To whom correspondence should be addressed. e-mail: davignj{at}ircm.qc.ca

The proprotein convertase subtilisin kexin-9 (PCSK9) circulates in plasma as mature and furin-cleaved forms. A polyclonal antibody against human PCSK9 was used to develop an ELISA that measures total plasma PCSK9 rather than only the mature form. A cross-sectional study evaluated plasma levels in normal (n = 254) and hypercholesterolemic (n = 200) subjects treated or untreated with statins or statin plus ezetimibe. In controls, mean plasma PCSK9 (89.5 ± 31.9 ng/ml) correlated positively with age, total cholesterol, LDL-cholesterol (LDL-C), triglycerides, and fasting glucose. Sequencing PCSK9 from individuals at the extremes of the normal PCSK9 distribution identified a new loss-of-function R434W variant associated with lower levels of circulating PCSK9 and LDL-C. In hypercholesterolemic subjects, PCSK9 levels were higher than in controls (99.3 ± 31.7 ng/ml, P < 0.04) and increased in proportion to the statin dose, combined or not with ezetimibe. In treated patients (n = 139), those with familial hypercholesterolemia (FH; due to LDL receptor gene mutations) had higher PCSK9 values than non-FH (147.01 ± 42.5 vs. 127.2 ± 40.8 ng/ml, P < 0.005), but LDL-C reduction correlated positively with achieved plasma PCSK9 levels to a similar extent in both subsets (r = 0.316, P < 0.02 in FH and r = 0.275, P < 0.009 in non-FH). The detection of circulating PCSK9 in both FH and non-FH subjects means that this assay could be used to monitor response to therapy in a wide range of patients.

Supplementary key words proprotein convertase subtilisin/kexin type 9 • LDL-cholesterol • hypercholesterolemia • hypocholesterolemia • ELISA • novel natural mutation • cardiovascular disease

Abbreviations: BMI, body mass index; CAD, coronary artery disease; FACS, fluorescence-activated cell sorting; FH, familial hypercholesterolemia; GOF, gain-of-function; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LOF, loss-of-function; PCSK9, proprotein convertase subtilisin/kexin type 9; rPCSK9, recombinant truncated human PCSK9; SREBP-2, sterol regulatory element binding protein-2; TC, total cholesterol; TG, triglyceride; WT, wild-type

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