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

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. 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. The familial hypercholesterolemia (FH) phenotype is characterized by elevated plasma LDL-cholesterol (LDL-C) levels, xanthomas, and premature atherosclerosis associated with increased risk of coronary artery disease (CAD). FH is caused primarily by loss-of-function (LOF) mutations in the LDL receptor gene (LDLR) responsible for the removal of plasma cholesterol, which is mainly found in LDL particles (1Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia.in: Valle D. Scriver C.R. Beaudet A.L. Sly W.S. Childs B. Volgestein B. The metabolic and molecular bases of inherited disease. McGraw Hill, New York2001: 2863-2913Google Scholar) or in the apolipoprotein B gene (2Innerarity T.L. Weisgraber K.H. Arnold K.S. Mahley R.W. Krauss R.M. Vega G.L. Grundy S.M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.Proc. Natl. Acad. Sci. USA. 1987; 84: 6919-6923Crossref PubMed Scopus (371) Google Scholar), the main protein component of LDL. In 2003, Abifadel et al. (3Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2188) Google Scholar) identified another protein associated with this phenotype, the proprotein convertase subtilisin/kexin-9 (PCSK9) (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (925) Google Scholar). The human PCSK9 gene (PCSK9) located on chromosome 1p32.3 is ∼22 kb long and comprises 12 exons encoding a 692 amino acid protein (5Seidah N.G. Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia.J. Mol. Med. 2007; 85: 685-696Crossref PubMed Scopus (135) Google Scholar). PCSK9 is expressed mainly in the liver, small intestine, and kidney (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (925) Google Scholar) and is thought to accelerate the degradation of hepatic LDLR in endosomes/lysosomes (6Nassoury N. Blasiole D.A. Tebon O.A. Benjannet S. Hamelin J. Poupon V. McPherson P.S. Attie A.D. Prat A. Seidah N.G. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR.Traffic. 2007; 8: 718-732Crossref PubMed Scopus (204) Google Scholar) by direct binding to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR (7Zhang D.W. Garuti R. Tang W.J. Cohen J.C. Hobbs H.H. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.Proc. Natl. Acad. Sci. USA. 2008; 105: 13045-13050Crossref PubMed Scopus (181) Google Scholar, 8Kwon H.J. Lagace T.A. McNutt J. for LDL receptor by Natl. Acad. Sci. USA. 2008; 105: PubMed Scopus Google Scholar). PCSK9 in and to LDLR levels and plasma LDL-C of low density lipoprotein receptor protein by proprotein convertase in PubMed Scopus Google Scholar, S. D. R. J. Wickham L. Hamelin J. Varret M. Allard D. et and its and on the low density lipoprotein receptor and LDL PubMed Scopus Google Scholar, J.L. of PCSK9 the degradation of the LDLR in a Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, J. of mutations in the PCSK9 gene on the LDL Mol. Genet. PubMed Scopus Google Scholar). of A. A. R. Marcinkiewicz J. A. Hamelin J. M. J. et convertase low-density lipoprotein receptor degradation and in liver 2008; PubMed Scopus Google Scholar) and human PCSK9 T.A. Garuti R. McNutt PCSK9 the of LDL in and of PubMed Scopus Google Scholar) in or human PCSK9 in kidney L. D. S. K.S. J. and distribution of circulating human PCSK9 expressed in PubMed Scopus Google Scholar) in a reduction of hepatic of plasma PCSK9 from human PCSK9 to a reduction in hepatic LDLR levels T.A. Garuti R. McNutt PCSK9 the of LDL in and of PubMed Scopus Google Scholar). of the gene to increased LDLR protein and plasma LDL-C A. A. R. Marcinkiewicz J. A. Hamelin J. M. J. et convertase low-density lipoprotein receptor degradation and in liver 2008; PubMed Scopus Google Scholar, S. Garuti R. plasma and to statins in Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). PCSK9 be by a proprotein its on LDLR S. D. Hamelin J. N. Seidah N.G. The proprotein convertase PCSK9 is by of mutations and PubMed Scopus Google Scholar). than amino acid of PCSK9 to plasma levels in (5Seidah N.G. Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia.J. Mol. Med. 2007; 85: 685-696Crossref PubMed Scopus (135) Google Scholar, Lagace T.A. L. Cohen J.C. Hobbs H.H. of loss-of-function mutations in PCSK9 and of a J. Genet. PubMed Scopus Google Scholar, A. A. Vega G.L. Cohen J.C. Hobbs H.H. A of PCSK9 to plasma levels of low-density lipoprotein J. Genet. PubMed Scopus Google Scholar, M. Rabes J.P. C. Varret M. the LDL receptor and apolipoprotein autosomal dominant hypercholesterolemia its 2007; PubMed Scopus Google Scholar). are as mutations are associated with levels of LDL-C and as mutations associated with low LDL-C. mutations in to In the total values as as S. K. S. A in PCSK9 hypercholesterolemia in a Genet. PubMed Scopus Google Scholar). The of in patients with be than in FH patients with LDLR mutations D. C. A.D. C. hypercholesterolemia in with the in the PCSK9 and treatment PubMed Scopus Google Scholar). the a study a risk of in of PCSK9 and or the mutations were associated with a reduction of plasma LDL-C and an reduction in the of coronary J.C. Hobbs H.H. in low and against coronary J. Med. PubMed Scopus Google Scholar). that study the of reduction of levels, a direct of PCSK9 was not a for mutations and in PCSK9 had a low plasma of LDL-C and circulating PCSK9 Lagace T.A. L. Cohen J.C. Hobbs H.H. of loss-of-function mutations in PCSK9 and of a J. Genet. PubMed Scopus Google Scholar). for the had a plasma LDL-C of A.D. The in PCSK9 is and in a 2007; PubMed Scopus Google Scholar). the that levels higher of plasma PCSK9 the levels of LDL-C and that of PCSK9 be in the of Cohen J.C. Hobbs H.H. a convertase that LDL PubMed Scopus Google Scholar). the is by a in of in J.L. and identified by in liver of 2003; PubMed Scopus Google Scholar, Brown M.S. J.L. of from and direct Natl. Acad. Sci. USA. 2003; 100: PubMed Scopus Google Scholar). is by in which that in human and human PCSK9 levels were increased by A. J. Seidah N.G. L. Prat A. the gene encoding the proprotein convertase neural apoptosis-regulated in familial PubMed Scopus Google Scholar). on the response of PCSK9 to therapy that statins and plasma PCSK9 levels J. A. M. A. M. Chretien M. PCSK9 levels are by statins and in 2008; PubMed Scopus Google Scholar, N. D. J. A. S. et PCSK9 with LDL and total in patients and are by 2008; PubMed Scopus Google Scholar, human levels of proprotein convertase 2008; PubMed Scopus Google Scholar). In the plasma PCSK9 by ELISA in and hypercholesterolemic patients. that plasma PCSK9 levels are correlated with and with levels of and fasting glucose. that PCSK9 levels are higher in hypercholesterolemic patients than in controls and higher in patients identified a R434W lower plasma levels of LDL-C and The is to be to a lower of from and on its on human PCSK9 was in and as (6Nassoury N. Blasiole D.A. Tebon O.A. Benjannet S. Hamelin J. Poupon V. McPherson P.S. Attie A.D. Prat A. Seidah N.G. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR.Traffic. 2007; 8: 718-732Crossref PubMed Scopus (204) Google Scholar). was by a to a polyclonal antibody to human PCSK9 The were by with and of the the were by a with the A of this antibody was with the from the antibody was from the were as S. D. Hamelin J. N. Seidah N.G. The proprotein convertase PCSK9 is by of mutations and PubMed Scopus Google Scholar) the and with to the were on and to a was used at a of The were by with on and were as S. D. Hamelin J. N. Seidah N.G. The proprotein convertase PCSK9 is by of mutations and PubMed Scopus Google Scholar, A. J. Seidah N.G. L. Prat A. the gene encoding the proprotein convertase neural apoptosis-regulated in familial PubMed Scopus Google Scholar). was a 12 were from of were not for or and from patients and were by at for at and lipoprotein and were at the of the a on a LDL-C was the were (n = S.M. J. of the of and lipoproteins assay of apolipoprotein B for of coronary disease a study in familial combined PubMed Scopus Google Scholar). subjects and the this was from to the The of the used for 12 exons were from at the for The were from and on a from were with assay were with of by at for in at The were with and for 1 at with were of in and were in and were for in a at to in The were at with of was for at with of ELISA was to was on a A was a human PCSK9 as S. Seidah N.G. is a protein that low density lipoprotein receptor 2008; PubMed Scopus Google Scholar). was by to a and PCSK9 from a in from The and were by amino acid in the of in at on a with a detection to a by C. PCSK9 was by to the was on plasma were used to the were with and as P < was by the of the was used to on PCSK9 were in patients had were with for or the variant at the with a (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (925) Google Scholar). the were for with and were with a and the by and by as (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (925) Google Scholar, S. D. R. J. Wickham L. Hamelin J. Varret M. Allard D. et and its and on the low density lipoprotein receptor and LDL PubMed Scopus Google Scholar). the of the R434W to were from with ELISA assay of the the of PCSK9 for The were with for 1 or and the were in and to an antibody the levels of of human PCSK9 in the of the mature and furin-cleaved PCSK9 S. D. Hamelin J. N. Seidah N.G. The proprotein convertase PCSK9 is by of mutations and PubMed Scopus Google Scholar), of which were in an PCSK9 are in the plasma of individuals an ELISA to circulating levels of PCSK9 in human plasma an polyclonal of this antibody was to and was by A was with and of the of human PCSK9 = was with to characterized by amino acid and of plasma were (n = and (n = A and was in plasma low of PCSK9 were to plasma and mean were and A plasma a PCSK9 a a range of to plasma were to to and PCSK9 by which is the range of the PCSK9 was in or plasma from and fasting plasma and PCSK9 levels are in was in plasma PCSK9 levels or in and in this of plasma PCSK9 levels by ELISA was higher values in both and The mean was ± and not and ± and ± ng/ml, both PCSK9 in subjects plasma values were at the of the values < or that low PCSK9 levels a (3Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2188) Google Scholar, A. A. Vega G.L. Cohen J.C. Hobbs H.H. A of PCSK9 to plasma levels of low-density lipoprotein J. Genet. PubMed Scopus Google Scholar) and A. A. Vega G.L. Cohen J.C. Hobbs H.H. A of PCSK9 to plasma levels of low-density lipoprotein J. Genet. PubMed Scopus Google Scholar, M. The in PCSK9 is associated with low plasma LDL-cholesterol in a PubMed Scopus Google or a variant R434W with mutations in the fasting plasma and PCSK9 levels of ± = = = ± ± ± 12 ± ± ± ± 31.9 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± in a new a with of the R434W or the that the of to PCSK9 is and the PCSK9 was lower in the R434W an lower of PCSK9 in the were by ELISA which at a lower of with the protein the of PCSK9 to that of the R434W variant to human hepatic with of PCSK9 from of or higher levels of the The were in and the by the were to to the levels of LDLR the The that 1 or the levels of were higher than those of the protein and that the that the was lower with the R434W that this a on the of the of the of the and the the lower of with a on its levels that a of this protein is in the a of the of of that with the R434W variant had of the a the variant in lower circulating levels of PCSK9 by a lower of the protein and a lower LDL-C to its on LDLR degradation PCSK9 levels and (r = P < LDL-C (r = P < (r = P < fasting (r = P < (r = P < and (r = P < was PCSK9 levels and (r = P = treatment as (n = or therapy (n = had on plasma PCSK9 levels of the are as and a to in a for the of an of The to PCSK9 levels that = fasting = = = for and = were that had a on PCSK9 levels in this of the PCSK9 individuals in plasma PCSK9 in patients the at the a patients were not on were on statin treatment on on on and on were on a and were on treatment patients had treated for at was in the PCSK9 and LDL-C to statin was a in the PCSK9 and the reduction in LDL-C. a plasma PCSK9 and the reduction of LDL-C from was (r = P < A PCSK9 plasma levels and in LDL-C was at statin (r = and for and the statins and for which had a of a in PCSK9 with statin in the of ezetimibe. was increased from to plasma PCSK9 levels increased from ± to ± (n = P for = by and for from to plasma PCSK9 increased from ± to ± (n = P for = by In treated patients (n = FH (n = subjects had higher PCSK9 values than non-FH (n = ± vs. ± ng/ml, P < plasma PCSK9 levels and LDL-C reduction correlated positively 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 that with or a statin combined with are associated with an in circulating levels of patients to LDL-C the mean plasma PCSK9 levels of controls, hypercholesterolemic patients patients on statin and on a higher plasma PCSK9 levels P < 0.04) in patients with patients on statin treatment a < higher plasma those on a combined treatment < higher levels that combined treatment was associated with higher mean plasma PCSK9 levels with of statin treatment = that is associated with higher levels of PCSK9 than those in controls and that patients on to lower LDL-C levels higher plasma PCSK9 In of the of LDL-C by this could in an response to PCSK9 is as an in and a for therapy and Cohen J.C. Hobbs H.H. a convertase that LDL PubMed Scopus Google Scholar, N.G. A. N. S. R. Prat A. The and of the proprotein J. 2008; PubMed Scopus Google Scholar, the of 2007; PubMed Scopus Google Scholar). a new ELISA to human plasma PCSK9 a polyclonal this plasma PCSK9 levels in a of from to ng/ml) and are correlated with both and LDL-C levels The with with a on a of plasma PCSK9 Lagace T.A. Cohen J.C. Hobbs H.H. levels of PCSK9 in a Scholar). to that that to as and are associated with higher circulating levels PCSK9 Lagace T.A. Cohen J.C. Hobbs H.H. levels of PCSK9 in a Scholar). was that in PCSK9 and the hepatic of C. S. C. M. A. C. M. B. et convertase subtilisin are from Scopus Google Scholar). The for PCSK9 to the polyclonal T.A. Garuti R. McNutt PCSK9 the of LDL in and of PubMed Scopus Google Scholar, N. D. J. A. S. et PCSK9 with LDL and total in patients and are by 2008; PubMed Scopus Google Scholar, J. proprotein convertase subtilisin is correlated with LDL 2007; PubMed Scopus (135) Google Scholar). a mean of in plasma with a range of T.A. Garuti R. McNutt PCSK9 the of LDL in and of PubMed Scopus Google Scholar), another a range of in mean J. proprotein convertase subtilisin is correlated with LDL 2007; PubMed Scopus (135) Google Scholar), and the a mean of and a range of N. D. J. A. S. et PCSK9 with LDL and total in patients and are by 2008; PubMed Scopus Google Scholar). a and et al. J. A. A. M. N. C. Seidah N.G. M. Chretien M. PCSK9 levels with in but not in 2007; PubMed Scopus Google Scholar) a mean of plasma PCSK9 of which is the found in this study but similar to that by et al. N. D. J. A. S. et PCSK9 with LDL and total in patients and are by 2008; PubMed Scopus Google Scholar). The are due to antibody and the used for the of used human PCSK9 as this was by amino acid and and by amino acid of a assay both and of PCSK9 the potential to the of both in to and in response to et al. J. A. A. M. N. C. Seidah N.G. M. Chretien M. PCSK9 levels with in but not in 2007; PubMed Scopus Google Scholar) found PCSK9 and levels in only a of not this in of found a with levels in both < and < be in to the of the of J. A. A. M. N. C. Seidah N.G. M. Chretien M. PCSK9 levels with in but not in 2007; PubMed Scopus Google Scholar) or in the in a et al. Lagace T.A. Cohen J.C. Hobbs H.H. levels of PCSK9 in a Scholar) that circulating PCSK9 levels are higher in than in and that is higher in the of PCSK9 in the with LDL-C was is and LDL-C by from to of L. S. A. A. for disease the in The Med. PubMed Scopus Google Scholar). with age, as of with a in and increased a PCSK9 and in with by plasma PCSK9 and in and (n = (n = (n = in a new study that of plasma PCSK9 levels in the of PCSK9 identified a new R434W of this variant that in a of a lower by and a lower of the degradation of LDLR in The lower in with the lower levels of circulating in this which is the mean of ± in normal subjects The of the is as this not to be in the direct of the domain of PCSK9 with the domain of the LDLR H.J. Lagace T.A. McNutt J. for LDL receptor by Natl. Acad. Sci. USA. 2008; 105: PubMed Scopus Google Scholar). The R434W variant in a in a the domain and the domain of PCSK9 D. J.L. T.A. et and of PCSK9 and its to familial hypercholesterolemia.Nat. Mol. 2007; PubMed Scopus Google Scholar) the domain is for the of the for degradation (7Zhang D.W. Garuti R. Tang W.J. Cohen J.C. Hobbs H.H. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.Proc. Natl. Acad. Sci. USA. 2008; 105: 13045-13050Crossref PubMed Scopus (181) Google Scholar), the R434W a and in a The in the of PCSK9 or is associated with another and this variant to be associated with low plasma PCSK9 levels, a that the that a in the could with protein M. L. Rabes J.P. J. A. M. Devillers M. Erlich D. et PCSK9 variant and familial combined Med. Genet. 2008; PubMed Scopus Google Scholar). A of PCSK9 ng/ml) was in an hypercholesterolemic of the variant in the the is in the is associated with a wide range of values A. A. Vega G.L. Cohen J.C. Hobbs H.H. A of PCSK9 to plasma levels of low-density lipoprotein J. Genet. PubMed Scopus Google Scholar). The PCSK9 in a of and hypercholesterolemia which is to but the not with the phenotype in the D. S. Abifadel M. M. Devillers M. M. J.P. A. et mutations of the PCSK9 gene cause phenotype of autosomal dominant PubMed Scopus Google Scholar). in is associated with low levels of LDL-C A. A. Vega G.L. Cohen J.C. Hobbs H.H. A of PCSK9 to plasma levels of low-density lipoprotein J. Genet. PubMed Scopus Google Scholar, D. S. Abifadel M. M. Devillers M. M. J.P. A. et mutations of the PCSK9 gene cause phenotype of autosomal dominant PubMed Scopus Google Scholar). Benjannet et al. S. D. Hamelin J. N. Seidah N.G. The proprotein convertase PCSK9 is by of mutations and PubMed Scopus Google Scholar) in that the in an protein that was to a of the main in this study was the levels of PCSK9 in patients treated with used statins and ezetimibe. that PCSK9 is in by statins A. J. Seidah N.G. L. Prat A. the gene encoding the proprotein convertase neural apoptosis-regulated in familial PubMed Scopus Google Scholar) a and increased levels J.L. and identified by in liver of 2003; PubMed Scopus Google Scholar, Brown M.S. J.L. of from and direct Natl. Acad. Sci. USA. 2003; 100: PubMed Scopus Google Scholar, human levels of proprotein convertase 2008; PubMed Scopus Google Scholar). The the of the in of PCSK9 protein in plasma in response to is in with the of et al. human levels of proprotein convertase 2008; PubMed Scopus Google Scholar) that plasma PCSK9 as LDL-C of that plasma PCSK9 is higher and statin are used in that the PCSK9 and the reduction in LDL-C is by the of as in the of statins the PCSK9 gene was in the S. Garuti R. plasma and to statins in Natl. Acad. Sci. USA. PubMed Scopus Google Scholar) and another the gene was by a in L. mutations in the PCSK9 gene are associated with and increased response to statin PubMed Scopus Google Scholar). increased to statin treatment PCSK9 was not expressed or expressed at low to the of on is that a of PCSK9 used in with statins LDL-C of an of was associated with higher PCSK9 levels PCSK9 is expressed in the small (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (925) Google Scholar), is of the of PCSK9 in this at in the is not a to circulating PCSK9 A. A. R. Marcinkiewicz J. A. Hamelin J. M. J. et convertase low-density lipoprotein receptor degradation and in liver 2008; PubMed Scopus Google Scholar). the levels of plasma PCSK9 associated with treatment from increased in the or in the liver, the main PCSK9 be to this on PCSK9 in A. A. R. Marcinkiewicz J. A. Hamelin J. M. J. et convertase low-density lipoprotein receptor degradation and in liver 2008; PubMed Scopus Google Scholar). PCSK9 in in subjects and found a of treatment with and M. S. D. et of on LDL receptor protein and on LDL receptor and gene a in 2008; PubMed Scopus Google Scholar). In with this of patients were on had a mean PCSK9 of ng/ml, to that of untreated hypercholesterolemic patients. was that with in a of plasma PCSK9 by the of in LDL-C and J. A. M. A. M. Chretien M. PCSK9 levels are by statins and in 2008; PubMed Scopus Google Scholar). was that treatment with the of PCSK9 by statins in lower LDL-C S. C. C. A.L. Ouguerram K. M. B. for the of proprotein convertase 2008; PubMed Scopus Google Scholar). In for the an ELISA that measures total PCSK9 in which the of the proportion of the mature protein and the by by the of a R434W variant a on LDLR is the that in with a statin is associated with a PCSK9 with the of to the statin on as by a A.L. of the of to statin Med. 2007; PubMed Scopus Google Scholar). the LDL-C in patients treatment an in PCSK9 levels, at PCSK9 be to the of in the is that a the of PCSK9 be and that for to and In that was that of a antibody that the to or in an in LDL-C and that in an the LDL-C by the statin J.C. D. C. Tang J. J. et the a proprotein convertase antibody in and Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). The the of the and and of and of The for the PCSK9 its coronary artery disease familial hypercholesterolemia LDL-cholesterol LDL receptor loss-of-function proprotein convertase human PCSK9 binding total

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