Journal
JOURNAL OF LIPID RESEARCH
Volume 51, Issue 1, Pages 140-149Publisher
ELSEVIER
DOI: 10.1194/jlr.M900273-JLR200
Keywords
proprotein convertase subtilisin/kexin type 9; LDL-cholesterol; hypercholesterolemia; hypocholesterolemia; ELISA; novel natural mutation; cardiovascular disease
Categories
Funding
- Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award
- CIHR [MOP 36496, CTP 82946]
- Canada chair [20652]
- Fonds de la Recherche en Sante du Quebec
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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.-Dubuc, G., M. Tremblay, G. Pare, H. Jacques, J. Hamelin, S. Benjannet, L. Boulet, J. Genest, L. Bernier, N. G. Seidah, and J. Davignon. A new method for measurement of total plasma PSCK9: clinical applications. J. Lipid Res. 2010. 51: 140-149.
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