LCAT plays a key role in the maturation of HDL, as evidenced by lowHDL-cholesterol levels in carriers of deleterious mutations inLCAT. However, the role of LCAT in atherosclerosis isunclear. We set out to study this in a prospective study. Plasma LCAT levels,which strongly correlate with LCAT activity, were measured in baselinenonfasting samples of 933 apparently healthy men and women who developedcoronary artery disease (CAD) and 1,852 matched controls who remained free ofCAD during 6 year follow-up. LCAT levels did not differ between cases andcontrols but were higher in women than men. Stratification into LCAT quartilesrevealed a positive association with plasma LDL-cholesterol and triglyceridelevels in the unexpected absence of an association with HDL-cholesterol. Inmixed-gender analyses, the odds ratio (OR) for future CAD in the highest LCATquartile versus the lowest was 1.00 [confidence interval (CI): 0.76–1.29,P for linearity = 0.902], although opposite trendswere observed in men and women. In fact, high LCAT levels were associated withan increased CAD risk in women (unadjusted OR 1.45, CI: 0.94–2.22,P for linearity = 0.036). In contrast to our studiesin carriers of LCAT mutations, the current data show that lowLCAT plasma levels are not associated with increased atherosclerosis in thegeneral population. LCAT plays a key role in the maturation of HDL, as evidenced by lowHDL-cholesterol levels in carriers of deleterious mutations inLCAT. However, the role of LCAT in atherosclerosis isunclear. We set out to study this in a prospective study. Plasma LCAT levels,which strongly correlate with LCAT activity, were measured in baselinenonfasting samples of 933 apparently healthy men and women who developedcoronary artery disease (CAD) and 1,852 matched controls who remained free ofCAD during 6 year follow-up. LCAT levels did not differ between cases andcontrols but were higher in women than men. Stratification into LCAT quartilesrevealed a positive association with plasma LDL-cholesterol and triglyceridelevels in the unexpected absence of an association with HDL-cholesterol. Inmixed-gender analyses, the odds ratio (OR) for future CAD in the highest LCATquartile versus the lowest was 1.00 [confidence interval (CI): 0.76–1.29,P for linearity = 0.902], although opposite trendswere observed in men and women. In fact, high LCAT levels were associated withan increased CAD risk in women (unadjusted OR 1.45, CI: 0.94–2.22,P for linearity = 0.036). In contrast to our studiesin carriers of LCAT mutations, the current data show that lowLCAT plasma levels are not associated with increased atherosclerosis in thegeneral population. LCAT hydrolyzes the sn-2 acyl group of phosphatidylcholine and subsequently transfers andesterifies the fatty acid to free cholesterol, thereby using apolipoprotein (apo) A-I ascofactor (1Glomset J.A. Verdery R.B. Role of LCAT in cholesterol metabolism.Expos. Annu. Biochim. Med. 1977; 33: 137-142PubMed Google Scholar). The reaction products are thuscholesteryl ester (CE) and lysophosphatidylcholine. The vast majority of CE in the bloodcirculation is generated by this enzymatic reaction. LCAT is primarily active on HDL andas such drives the maturation of small nascent HDL discs to larger spherical HDL (2Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer H.B. Lecithin cholesterol acyltransferase deficiency and fish eyedisease. In The Online Metabolic and Molecular Bases ofInherited Diseases (OMMBID). Part 12: Lipids. 2001Google Scholar). In catalyzing the esterification of freecholesterol, LCAT has been proposed to maintain a concentration gradient of freecholesterol from cells to HDL, thereby facilitating reverse cholesterol transport (3Glomset J.A. The plasma lecithins:cholesterolacyltransferase reaction.J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar, 4Fielding C.J. Fielding P.E. Cellular cholesterol efflux.Biochim.Biophys. Acta. 2001; 1533: 175-189Crossref PubMed Scopus (153) Google Scholar).LCAT-deficient patients present with almost complete HDL deficiency because they areunable to form mature HDL, which in turn leads to a rapid clearance of nascent HDL fromthe circulation (2Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer H.B. Lecithin cholesterol acyltransferase deficiency and fish eyedisease. In The Online Metabolic and Molecular Bases ofInherited Diseases (OMMBID). Part 12: Lipids. 2001Google Scholar, 5Kuivenhoven J.A. Pritchard H. Hill J. Frohlich J. Assmann G. Kastelein J. The molecular pathology oflecithin:cholesterol acyltransferase (LCAT) deficiencysyndromes.J. Lipid Res. 1997; 38: 191-205Abstract Full Text PDF PubMed Google Scholar). Based on our current understanding of HDL metabolism, it is not clear whether LCAT ispro- or anti-atherogenic (6Jonas A. Lecithin cholesterolacyltransferase.Biochim. Biophys. Acta. 2000; 1529: 245-256Crossref PubMed Scopus (288) Google Scholar, 7Rousset X. Vaisman B. Amar M. Sethi A.A. Remaley A.T. Lecithin: cholesterol acyltransferase–from biochemistryto role in cardiovascular disease.Curr. Opin.Endocrinol. Diabetes Obes. 2009; 16: 163-171Crossref PubMed Scopus (117) Google Scholar): the generation of CE on HDL by LCAT can beregarded as anti-atherogenic since this action increases HDL cholesterol (HDL-C) levels,but in the presence of cholesteryl ester transfer protein (CETP) and triglyceride-richlipoproteins, the CE will be transferred to apoB-containing lipoproteins that areatherogenic. Animal studies have, unfortunately, not provided clear answers: both LCATknockout mice and LCAT overexpression models yielded mixed results with respect toatherogenesis, as recently reviewed by Ng (8Ng D.S. Insight into the role of LCAT from mousemodels.Rev. Endocr. Metab. Disord. 2004; 5: 311-318Crossref PubMed Scopus (28) Google Scholar).Recently, Amar, Shamburek, and Vaisman (9Amar M.J. Shamburek R.D. Vaisman B. Knapper C.L. Foger B. Hoyt Jr., R.F. Santamarina-Fojo S. Brewer Jr., H.B. Remaley A.T. Adenoviral expression of human lecithin-cholesterolacyltransferase in nonhuman primates leads to an antiatherogenic lipoproteinphenotype by increasing high-density lipoprotein and lowering low-densitylipoprotein.Metabolism. 2009; 58: 568-575Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar)studied adenoviral expression of human LCAT in squirrel monkeys, which express CETP at alevel comparable to humans and develop diet-induced atherosclerosis. In this study,overexpression of LCAT led to an antiatherogenic lipoprotein phenotype by increasingHDL-C and lowering LDL-cholesterol (LDL-C). Contrary to the numerous animal studies on LCAT and atherosclerosis, only very fewstudies were carried out in humans, but these have also provided conflicting results(5Kuivenhoven J.A. Pritchard H. Hill J. Frohlich J. Assmann G. Kastelein J. The molecular pathology oflecithin:cholesterol acyltransferase (LCAT) deficiencysyndromes.J. Lipid Res. 1997; 38: 191-205Abstract Full Text PDF PubMed Google Scholar, 10Santamarina-Fojo S. Lambert G. Hoeg J.M. Brewer Jr, H.B. Lecithin-cholesterol acyltransferase: rolein lipoprotein metabolism, reverse cholesterol transport andatherosclerosis.Curr. Opin. Lipidol. 2000; 11: 267-275Crossref PubMed Scopus (82) Google Scholar, 11Dullaart R.P. Perton F. Sluiter W.J. deVries R. vanTol A. Plasma lecithin: cholesterolacyltransferase activity is elevated in metabolic syndrome and is anindependent marker of increased carotid artery intima mediathickness.J. Clin. Endocrinol. Metab. 2008; 93: 4860-4866Crossref PubMed Scopus (44) Google Scholar, 12Solajic-Bozicevic N. Stavljenic-Rukavina A. Sesto M. Lecithin-cholesterol acryltransferaseactivity in patients with coronary artery disease examined by coronaryangiography.Clin. Investig. 1994; 72: 951-956Crossref PubMed Scopus (25) Google Scholar, 13Solajic-Bozicevic N. Stavljenic A. Sesto M. Lecithin: cholesterol acyltransferaseactivity in patients with acute myocardial infarction and coronary heartdisease.Artery. 1991; 18: 326-340PubMed Google Scholar, 14Dobiasova M. Lecithin: cholesterol acyltransferase and theregulation of endogenous cholesterol transport.Adv.Lipid Res. 1983; 20: 107-194PubMed Google Scholar, 15Hovingh G.K. Hutten B.A. Holleboom A.G. et al.Compromised LCAT function is associated with increasedatherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (132) Google Scholar). Genetic associationstudies have, historically, not been performed due to the lack of frequent LCAT genevariation in the general population. Recently, however, genome-wide association studiesreported two single nucleotide polymorphisms (SNPs) near the LCAT gene locus that wereassociated with HDL-C levels (16Kathiresan S Willer C.J. Peloso G.M. et al.Common variants at 30 loci contribute to polygenicdyslipidemia.Nat. Genet. 2009; 41: 56-65Crossref PubMed Scopus (1018) Google Scholar, 17Willer C.J. Sanna S. Jackson A.U. et al.Newly identified loci that influence lipid concentrations andrisk of coronary artery disease.Nat.Genet. 2008; 40: 161-169Crossref PubMed Scopus (1223) Google Scholar). Willer, Sanna, and Jackson (17Willer C.J. Sanna S. Jackson A.U. et al.Newly identified loci that influence lipid concentrations andrisk of coronary artery disease.Nat.Genet. 2008; 40: 161-169Crossref PubMed Scopus (1223) Google Scholar) showed that the rs255052 SNP, located 49 kbdownstream of LCAT, had an effect size on HDL-C of +0.019 mmol/l, while this SNPwas not found associated with coronary artery disease (CAD). Another recent articledescribed a SNP 7.7 kb upstream of LCAT to be correlated with HDL-C, but this effect wasnot reproduced in another cohort (18Pare G. Serre D. Brisson D. et al.Genetic analysis of 103 candidate genesfor coronary artery disease and associated phenotypes in a founderpopulation reveals a new association between endothelin-1 and high-densitylipoprotein cholesterol.Am. J. Hum. Genet. 2007; 80: 673-682Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). To date,it remains to be shown whether these SNPs are indeed associated with transcriptionalchanges at the LCAT gene locus. Large LCAT studies using biochemical means have been difficult to conduct because LCATactivity measurements are cumbersome and time-consuming (19Jonas A. Regulation of lecithin cholesterolacyltransferase activity.Prog. Lipid Res. 1998; 37: 209-234Crossref PubMed Scopus (94) Google Scholar). In this light, only two reports on small cross-sectionalstudies have shown that LCAT activity is low in patients with either angiographicallydocumented CAD (12Solajic-Bozicevic N. Stavljenic-Rukavina A. Sesto M. Lecithin-cholesterol acryltransferaseactivity in patients with coronary artery disease examined by coronaryangiography.Clin. Investig. 1994; 72: 951-956Crossref PubMed Scopus (25) Google Scholar) or acute myocardialinfarction (13Solajic-Bozicevic N. Stavljenic A. Sesto M. Lecithin: cholesterol acyltransferaseactivity in patients with acute myocardial infarction and coronary heartdisease.Artery. 1991; 18: 326-340PubMed Google Scholar). Finally, the use of LCATplasma levels as a tool was until recently very limited due to the absence ofcommercially available LCAT antibodies. Families with LCAT deficiency syndromes havethus far been one of the few sources to study LCAT and atherosclerosis in man. We havepreviously shown that loss of LCAT function in carriers of LCAT gene mutations isassociated with an increased carotid intima media thickness, a surrogate marker forcardiovascular endpoints (15Hovingh G.K. Hutten B.A. Holleboom A.G. et al.Compromised LCAT function is associated with increasedatherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (132) Google Scholar). To shed morelight on the role of LCAT in human atherosclerosis, the objective of this study was toassess the association between plasma LCAT levels and risk of future CAD events in alarge cohort representing the general population. A prospective nested case-control study was performed among participants of theEuropean Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolkstudy. The EPIC-Norfolk cohort has been described in detail (20Day N. Oakes S. Luben R. et al.EPIC-Norfolk: study design andcharacteristics of the cohort. European Prospective Investigation ofCancer.Br. J. Cancer. 1999; 80: 95-103PubMed Google Scholar). For this analysis, only individualswho did not report a history of heart attack or stroke at the baseline clinicvisit were enrolled, while participants treated with lipid-lowering medicationat baseline were excluded. Cases were 993 individuals who had a hospitaladmission and/or died from CAD as underlying cause during follow-up (average of6 years). CAD was defined as code 410 to 414 according to InternationalClassification of Diseases-9th revision. Controls (n = 1,852) wereindividuals who remained free of CAD during follow-up. Two controls were matchedto each case for sex, age (within 5 years), general practice, and time ofenrolment (within 3 months). The study was approved by the Norwich DistrictHealth Authority Ethics Committee, and all participants gave signed informedconsent. Nonfasting blood samples were drawn into plain and citrate bottles. Blood sampleswere processed directly at the Department of Clinical Biochemistry, Universityof Cambridge, or stored at −80°C. Serum levels of total cholesterol,HDL-C, and triglycerides were measured in fresh samples with the RA 1000 (BayerDiagnostics, Basingstoke, UK). LDL-C levels were calculated using the Friedewaldformula. Serum levels of apoA-I and apoB were measured by rateimmunonephelometry (Behring Nephelometer BNII, Marburg, Germany) withcalibration traceable to the International of Clinical H. International of for measurements of B. and of candidate 38: PubMed Scopus Google Scholar). of were measured with a on and size of and HDL were measured by analysis by Med. Full Text Full Text PDF PubMed Scopus Google Scholar). was performed as described et levels in small the risk heart disease in the EPIC-Norfolk prospective J. 2007; PubMed Scopus Google Scholar, M. A. B. A new for HDL gradient using Lipid Res. 2001; Full Text Full Text PDF PubMed Google Scholar). CETP concentrations were measured with a R.P. et al.Common cholesteryl ester transfer protein gene the effect of in PubMed Scopus Google Scholar). measured in using a available LCATplasma levels were measured using a available which has been described in detail S. M. A new two to Full Text Full Text PDF PubMed Google Scholar). on the LCAT of with of from EPIC-Norfolk carried out in to and were in were between cases and controls using and the for LCAT levels were as on the of LCAT levels in of LCAT plasma were and risk were calculated using and the for In to the between LCAT levels and analysis was to and as of the risk of into the sex, and The lowest was as The were for the cardiovascular risk risk blood HDL-C, and were performed using A was to be A total of out of 933 cases died of the from CAD and and LCAT levels of cases and controls data Cases had a higher to to have and levels of total cholesterol, and and blood were higher than in while HDL-C and apoA-I levels were of cases and matched and blood blood and cholesterol were matched to cases for sex, and as with in or as of the total are on or for on and of data on were to a in a new Controls were matched to cases for sex, and as with in or as of the total are on or for on and of data on were to a In our and of for were and data were measurements of LCAT concentration in the plasma healthy in our in this stored in for single use et S. M. A new two to Full Text Full Text PDF PubMed Google Scholar) between LCAT concentration measurements with LCAT with a = or endogenous We this by the and LCAT activity in plasma of for a in the LCAT gene of the mature LCAT a protein J.A. H. Pritchard et in a is cause of an human Clin. PubMed Scopus Google Scholar). were and with in LCAT levels were and of in these are in with our measurements using a LCAT concentration with in apparently healthy controls S. M. A new two to Full Text Full Text PDF PubMed Google Scholar). this of LCAT concentration is to the in these with controls the Plasma LCAT levels were and were to in controls = only the were observed cases and = however, LCAT levels to be higher in cases in = cases and controls LCAT levels were in women with men versus of of LCAT levels with cardiovascular and lipid LCAT levels were associated with LCAT levels were associated with and both blood The of did not differ among LCAT levels were associated with total cholesterol, In the and apoB levels associated with LCAT levels and data for The of LCAT with age be to observed the LCAT and and (n = (n = (n = (n = for of risk levels LCAT levels and risk and the LCAT levels and risk and the for by between LCAT levels and and the cholesterol, between LCAT levels and and the are or and for of risk levels LCAT levels and risk and the for by between LCAT levels and and the in a new are or and We did not a between LCAT levels and HDL-C women or both were 3 LCAT levels and lipid LCAT was correlated with HDL size and size as by gradient and LCAT levels were with and of LCAT levels with lipoprotein and and HDL, HDL, HDL, small gradient with in a new gradient with In a analysis, LCAT were not associated with the risk ofCAD = the versus for linearity the for risk did not this = for a of versus = for CAD LCAT for cohort and men and for risk risk sex, total cholesterol, and blood and the presence for risk risk sex, total cholesterol, and blood and the presence for risk risk sex, total cholesterol, and blood and the presence for the risk of future CAD events for both and women The are in for for of risk sex, total cholesterol, and blood and the presence in a new for the risk of future CAD events for both and women The are in for for of For the risk of CAD with increasing LCAT for the risk = for a of versus for linearity = In the CAD in women increased with increasing LCAT levels = for a of versus for linearity = 0.036). However, the risk this was = for plasma CETP levels did not of the the prospective analysis for the time that low plasma levels of LCAT associated with an increased risk of future CAD in the general a effect was identified that not our of increased atherosclerosis with a loss of LCAT function (15Hovingh G.K. Hutten B.A. Holleboom A.G. et al.Compromised LCAT function is associated with increasedatherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (132) Google Scholar). The current show that LCAT levels associated with blood total cholesterol, and in the absence of an association with The absence of an association between plasma LCAT levels and HDL-C was by et Lecithin: cholesterol acyltransferase (LCAT) to LCAT activity and cholesterol Lipid Res. Full Text PDF PubMed Google Scholar, for lecithin-cholesterolacyltransferase Full Text PDF PubMed Scopus Google Scholar) in both but not in two small studies a positive between LCAT LCAT activity, and HDL-C J. of high lipoprotein acyltransferase concentration Full Text PDF PubMed Scopus Google Scholar, of lecithin: cholesterol acyltransferase concentrations with and plasma concentrations in Full Text PDF PubMed Scopus Google Scholar). the results of the current larger analysis, it be that LCAT concentration LCAT activity, but is from studies S. M. A new two to Full Text Full Text PDF PubMed Google Scholar, Lecithin: cholesterol acyltransferase (LCAT) to LCAT activity and cholesterol Lipid Res. Full Text PDF PubMed Google Scholar, for lecithin-cholesterolacyltransferase Full Text PDF PubMed Scopus Google Scholar) that it this by LCAT activity and LCAT plasma for a in LCAT that of the mature LCAT can also be that the is not a in HDL but this not the that loss of LCAT function of levels in with LCAT gene the it shown that SNPs near the LCAT gene locus are associated with but it remains to be shown whether these SNP are indeed associated of the LCAT gene (16Kathiresan S Willer C.J. Peloso G.M. et al.Common variants at 30 loci contribute to polygenicdyslipidemia.Nat. Genet. 2009; 41: 56-65Crossref PubMed Scopus (1018) Google Scholar, 17Willer C.J. Sanna S. Jackson A.U. et al.Newly identified loci that influence lipid concentrations andrisk of coronary artery disease.Nat.Genet. 2008; 40: 161-169Crossref PubMed Scopus (1223) Google Scholar). The positive association of LCAT levels with LDL-C levels in this study the of et Lecithin: cholesterol acyltransferase (LCAT) to LCAT activity and cholesterol Lipid Res. Full Text PDF PubMed Google Scholar, for lecithin-cholesterolacyltransferase Full Text PDF PubMed Scopus Google Scholar). LCAT deficiency present with LDL-C levels J.A. Pritchard H. Hill J. Frohlich J. Assmann G. Kastelein J. The molecular pathology oflecithin:cholesterol acyltransferase (LCAT) deficiencysyndromes.J. Lipid Res. 1997; 38: 191-205Abstract Full Text PDF PubMed Google while in humans that of plasma CE are on apoB-containing A.G. Pritchard International on on a Lipid Res. Full Text PDF PubMed Google Scholar). We also show that plasma triglycerides and associated with plasma LCAT which an association that was recently between LCAT activity of the metabolic syndrome R.P. Perton F. Sluiter W.J. deVries R. vanTol A. Plasma lecithin: cholesterolacyltransferase activity is elevated in metabolic syndrome and is anindependent marker of increased carotid artery intima mediathickness.J. Clin. Endocrinol. Metab. 2008; 93: 4860-4866Crossref PubMed Scopus (44) Google Scholar). The that increased LCAT a the this is be from study that plasma LCAT levels not risk of future is not on the of our of intima media in carriers of LCAT gene with (15Hovingh G.K. Hutten B.A. Holleboom A.G. et al.Compromised LCAT function is associated with increasedatherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (132) Google Scholar). be by of LCAT in our while the of LCAT concentration is by the a showed a positive association of LCAT levels with carotid patients with the metabolic syndrome as as in R.P. Perton F. Sluiter W.J. deVries R. vanTol A. Plasma lecithin: cholesterolacyltransferase activity is elevated in metabolic syndrome and is anindependent marker of increased carotid artery intima mediathickness.J. Clin. Endocrinol. Metab. 2008; 93: 4860-4866Crossref PubMed Scopus (44) Google Scholar). that LCAT activity was in patients with CAD (12Solajic-Bozicevic N. Stavljenic-Rukavina A. Sesto M. Lecithin-cholesterol acryltransferaseactivity in patients with coronary artery disease examined by coronaryangiography.Clin. Investig. 1994; 72: 951-956Crossref PubMed Scopus (25) Google Scholar) and in patients with infarction (13Solajic-Bozicevic N. Stavljenic A. Sesto M. Lecithin: cholesterol acyltransferaseactivity in patients with acute myocardial infarction and coronary heartdisease.Artery. 1991; 18: 326-340PubMed Google Scholar, 14Dobiasova M. Lecithin: cholesterol acyltransferase and theregulation of endogenous cholesterol transport.Adv.Lipid Res. 1983; 20: 107-194PubMed Google Scholar). these small studies prospective it can be that LCAT activity be acute of a myocardial in with HDL-C but time S. S. The esterification of cholesterol acute myocardial PubMed Google Scholar). showed that higher LCAT levels in women wereassociated with an increased risk of In the an was is that the opposite and women the absence of a between LCAT levels and CAD this have for this women were at and it be prospective of this study Plasma levels of in a however, studies report of or on LCAT (19Jonas A. Regulation of lecithin cholesterolacyltransferase activity.Prog. Lipid Res. 1998; 37: 209-234Crossref PubMed Scopus (94) Google Scholar). a single of LCAT plasma the role of this in the of lipid and associated atherosclerosis. CAD and which in or in this study however, high of such et and the risk infarction or due to coronary artery disease in myocardial infarction or the EPIC-Norfolk J. Med. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Finally, for but by or be excluded. However, this is a of a study. In this has recently been found to LCAT activity D. A. G. of reverse cholesterol with metabolic syndrome 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). treated were from this analysis, the of such during follow-up be a of study that low plasma LCAT levels low LCAT are with an increased risk of future CAD in the general population. be to opposite in both that this not our of increased in our studiesin with LCAT gene mutations (15Hovingh G.K. Hutten B.A. Holleboom A.G. et al.Compromised LCAT function is associated with increasedatherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (132) Google Scholar).
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