Background A low plasma level of low-density lipoprotein (LDL)cholesterol is associated with reduced risk of coronary heartdisease (CHD), but the effect of lifelong reductions in plasmaLDL cholesterol is not known. We examined the effect of DNA-sequencevariations that reduce plasma levels of LDL cholesterol on theincidence of coronary events in a large population.
Methods We compared the incidence of CHD (myocardial infarction,fatal CHD, or coronary revascularization) over a 15-year intervalin the Atherosclerosis Risk in Communities study according tothe presence or absence of sequence variants in the proproteinconvertase subtilisin/kexin type 9 serine protease gene (PCSK9)that are associated with reduced plasma levels of LDL cholesterol.
Results Of the 3363 black subjects examined, 2.6 percent hadnonsense mutations in PCSK9; these mutations were associatedwith a 28 percent reduction in mean LDL cholesterol and an 88percent reduction in the risk of CHD (P=0.008 for the reduction;hazard ratio, 0.11; 95 percent confidence interval, 0.02 to0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percenthad a sequence variation in PCSK9 that was associated with a15 percent reduction in LDL cholesterol and a 47 percent reductionin the risk of CHD (hazard ratio, 0.50; 95 percent confidenceinterval, 0.32 to 0.79; P=0.003).
Conclusions These data indicate that moderate lifelong reductionin the plasma level of LDL cholesterol is associated with asubstantial reduction in the incidence of coronary events, evenin populations with a high prevalence of non–lipid-relatedcardiovascular risk factors.
Experimental, genetic, and epidemiologic data support the conceptthat an elevated plasma level of low-density lipoprotein (LDL)cholesterol is a primary causal factor in the pathogenesis ofcoronary heart disease (CHD). Population-based studies consistentlydemonstrate a positive correlation between plasma levels ofLDL cholesterol and the prevalence of CHD, and all five single-genedisorders that result in elevated LDL levels are associatedwith premature coronary atherosclerosis.1
The question regarding the reverse situation naturally arises.If elevations in LDL cholesterol cause CHD, do reductions inLDL cholesterol prevent this disease? Reductions in plasma LDLcholesterol levels have been strongly associated with a reducedincidence of coronary events in clinical trials,2 but the long-termeffects of low LDL cholesterol levels on coronary atherosclerosishave been less clearly defined. Data from cross-sectional andcohort studies are consistent with the hypothesis that low levelsof LDL cholesterol are protective,3 but these data are potentiallyconfounded by other factors related to low LDL cholesterol levelsthat may independently contribute to reductions in cardiovascularevents. Studies of genetic disorders that specifically lowerthe plasma level of LDL cholesterol, such as heterozygous familialhypobetalipoproteinemia, would provide an ideal system in whichto assess the consequences of low LDL cholesterol levels independentlyof other factors that may modify disease progression. Thesedisorders are uncommon and genetically heterogeneous, however,and it has not been possible to determine their effects on CHD.
Recently, we found that approximately 2 percent of black subjectshave one of two nonsense mutations (426CG, encoding Y142X [replacementof the tyrosine at position 142 with a stop codon], and 2037CA,encoding C679X [replacement of the cysteine at position 679with a stop codon]) in PCSK9, the proprotein convertase subtilisin/kexintype 9 serine protease gene.4 These two nonsense mutations areassociated with a 40 percent reduction in mean LDL cholesterol.4Both nonsense mutations are rare among white subjects. We alsoidentified a PCSK9 sequence variation (137GT, encoding R46L[replacement of the arginine at position 46 with leucine]) thatis more common among white subjects (prevalence, 3.2 percent)than among black subjects (0.6 percent) and that is associatedwith a 21 percent decrease in plasma LDL cholesterol levels.5
The molecular mechanisms by which these sequence variationsin PCSK9 reduce the LDL cholesterol level are not known. PCSK9is a glycoprotein that is expressed at its highest levels inthe liver, intestine, and kidney.6 Overexpression of PCSK9 orthe mouse orthologue in the livers of mice results in a markedreduction in LDL receptors in this organ,7,8,9,10 which is themain pathway for the removal of LDL from the plasma, and a correspondingincrease in circulating LDL cholesterol levels. Conversely,mice lacking Pcsk9 have increased levels of hepatic LDL receptors,and they remove LDL from the plasma at an accelerated rate.11Thus, high levels of PCSK9 lead to high plasma levels of LDLcholesterol, whereas low levels of PCSK9 lead to low LDL cholesterollevels.
The relatively high prevalence of LDL-lowering sequence variationsin PCSK9 provided the opportunity to analyze the effects ofspecific, lifelong reduction in LDL cholesterol levels on therisk of CHD. Here we report the effects of these sequence variationson the incidence of CHD in the Atherosclerosis Risk in Communities(ARIC) study, a longitudinal, biracial cohort study designedto assess subclinical and clinical atherosclerosis.12
Methods
Subjects
The ARIC study is a prospective study of atherosclerosis initiatedin 1987. The study comprises four communities (Jackson, Miss.;Minneapolis; Forsyth County, N.C.; and Washington County, Md.),each of which recruited a randomly selected cohort of approximately4000 persons 45 to 64 years of age.12 The subjects participatedin four triennial examinations and were interviewed annuallyby telephone. Records of hospitalizations and deaths were abstractedas previously described.13 The follow-up data in this studyinclude events up to January 1, 2003. The protocol for the studywas approved by the institutional review boards of all centers,and all participants provided written informed consent thatincluded consent for genetic studies.
A total of 15,792 participants underwent an extensive initialexamination, which included collection of medical, social, anddemographic data. Race or ethnic group was determined by self-identification;participants described themselves as black or white in responseto a questionnaire on which the available categories were black,white, Indian, or Asian. The data used in this study includedthe data from black participants (predominantly, those livingin Jackson) and white participants in whom lipoproteins weremeasured after a fast at baseline and subsequently monitored.The exclusion criteria included use of lipid-lowering drugs(454 persons) and the presence of symptomatic cardiovasculardisease (1430 persons) at baseline. Plasma lipids and lipoproteinswere assayed in the ARIC central lipid laboratory with commercialreagents, as previously described.14 The lipid and lipoproteinlevels and risk-factor profiles used in this study were obtainedat baseline. Hypertension was defined by a systolic blood pressureof 140 mm Hg or higher, a diastolic blood pressure of 90 mmHg or higher, or use of antihypertensive medication. Diabetesmellitus was defined by a fasting glucose level of 126 mg perdeciliter (7 mmol per liter) or higher, a nonfasting glucoselevel of 200 mg per deciliter (11 mmol per liter) or higher,use of hypoglycemic agents, or a history of physician-diagnoseddiabetes mellitus. Cigarette smoking was assessed by standardizedquestionnaires, and current smokers were classified as positivefor smoking.
CHD and Carotid-Artery Intima–Media Thickness
The incidence of CHD was determined by contacting participantsannually, by identifying hospitalizations and deaths duringthe previous year, and by surveying discharge lists from localhospitals and death certificates from state vital-statisticsoffices for potential cardiovascular events. All cardiovascularevents were adjudicated by independent physician-scientists,as described previously.15 CHD was defined as a definite orprobable myocardial infarction, a silent myocardial infarctiondetected by electrocardiographic interval changes consistentwith an intercurrent ischemic event, death due to CHD, or acoronary-revascularization procedure (coronary bypass graft,coronary angioplasty, or coronary atherectomy). Carotid-arteryintima–media thickness, a measure of subclinical atherosclerosisthat predicts incident CHD,13 was determined at baseline withthe use of B-mode ultrasonography, as previously described.16
Genotyping
Fluorogenic 5'-nucleotidase assays for the PCSK9 alleles encodingY142X, C679X, and R46L were developed with the use of the TaqMansystem (Applied Biosystems). The assays were performed on a7900HT Fast Real-Time PCR instrument with probes and reagentspurchased from Applied Biosystems. Among the 13,761 eligiblesubjects (10,045 whites and 3716 blacks), there were 419 (255whites and 164 blacks) from whom genomic DNA was not available,and genotypes were missing because of assay failure for theR46L variant (2.9 percent), the Y142X variant (2.7 percent),and the C679X variant (2.9 percent). The ARIC genotyping laboratoryuses a 5 percent blind replicate quality-assurance program forgenotype determinations; the agreement for the variants describedhere was 100 percent.
Statistical Analysis
Routine comparisons of risk-factor levels between carriers ofa PCSK9 variant and noncarriers were performed with contingencychi-square tests for discrete variables and t-tests for continuousvariables. The number of coronary events was not adjusted accordingto age and sex because these variables did not differ betweencarriers and noncarriers. Cox proportional-hazards modelingwas used to test the null hypothesis that the incidence rateof CHD did not differ between carriers and noncarriers. In thisanalysis, the dependent variable was the time to an event. Theanalysis properly accounted for participants who were lost tofollow-up or who had not had an event by the end of the studyperiod. Therefore, the analysis included all eligible personswho entered the follow-up period, except for 45 persons whospecifically asked that their DNA not be used for research.Hazard ratios based on the regression coefficients from theCox modeling procedure are reported.
Results
The frequencies of the PCSK9142X and the PCSK9679X alleles amongblack subjects were 0.8 percent and 1.8 percent, respectively(Table 1). Thus, approximately 1 of every 40 black subjectsin the ARIC study had a nonsense mutation in PCSK9 — afrequency similar to that observed in two other populations.4Both nonsense mutations were rare among white subjects: of 9537white subjects tested, only 2 had the PCSK9142X allele and 4had the PCSK9679X allele. Therefore, analysis of these nonsensemutations was restricted to black subjects. The prevalence ofnon–lipid-related risk factors was similar in carriersand noncarriers, with the exception of hypertension, which wasmore common in noncarriers (55 percent vs. 37 percent, P=0.001)(Table 1). Plasma levels of total cholesterol, triglycerides,and LDL cholesterol were significantly lower among subjectswith a nonsense mutation in PCSK9, but the levels of high-densitylipoprotein (HDL) cholesterol were similar in carriers and noncarriers.
Table 1. Nonsense Mutations in PCSK9 and Cardiovascular Risk Factors among 3363 Black Participants in the Study.
The distribution of plasma levels of LDL cholesterol among blackcarriers of a PCSK9 variant was shifted toward lower levels(Figure 1A). The mean plasma LDL cholesterol level was 28 percentlower in the carriers than in the noncarriers (Table 1). Notall subjects with a nonsense mutation had a low plasma levelof LDL cholesterol (the levels ranged from 36 to 258 mg perdeciliter [0.9 to 6.7 mmol per liter]), but 81 percent had anLDL cholesterol level below the 50th percentile for black subjects.
Figure 1. Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a PCSK9142X or PCSK9679X Allele.
In Panel A, the distribution of plasma LDL cholesterol levels at baseline among 3278 black subjects who did not have a PCSK9142X or PCSK9679X allele (top) is compared with the distribution of levels among the 85 black subjects who had one of these two alleles (bottom). Panel B shows the percentage of participants from these two groups who had no evidence of coronary heart disease at baseline and in whom coronary heart disease developed during the 15-year follow-up period. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586.
Among black subjects who did not have a nonsense mutation, 9.7percent had a coronary event during the 15-year follow-up period(Figure 1B). In contrast, CHD developed in only 1 of the 85black participants (1.2 percent) who had a nonsense mutation(P=0.008). According to Cox proportional-hazards modeling, thehazard ratio for CHD among carriers as compared with noncarriers,after adjustment for age and sex, was 0.11 (95 percent confidenceinterval, 0.02 to 0.81; P=0.03). The incidence of disease remainedsignificantly lower among carriers than among noncarriers (P<0.05)when hypertension and diabetes were added to the model. Theonly carrier in whom CHD developed was a black man who was obese(body-mass index [the weight in kilograms divided by the squareof the height in meters], 34), had hypertension (blood pressure,186/85 mm Hg), and was a smoker. He also had an Lp(a) lipoproteinlevel above the 95th percentile for his race and sex as wellas a family history of CHD. Despite a very low plasma levelof LDL cholesterol (53 mg per deciliter [1.4 mmol per liter]),he died at the age of 68 years, within 24 hours after his firstmyocardial infarction.
The frequency of PCSK946L heterozygosity was 3.2 percent amongwhite subjects (Table 2) and 0.7 percent among black subjects.A total of eight white subjects were homozygous for the PCSK946Lallele. The age, sex distribution, body-mass index, and prevalencesof hypertension, diabetes, and smoking were not significantlydifferent between white subjects with the PCSK946L allele andthose without it (Table 2). As was observed for the nonsensemutations, the R46L substitution was associated with a significantreduction in plasma levels of total cholesterol (9 percent)and LDL cholesterol (15 percent). The mean plasma level of LDLcholesterol was slightly lower among the 8 white subjects whowere homozygous for the PCSK946L allele than among the 293 whitesubjects who were heterozygotes (112±46 mg per deciliter[2.9±1.2 mmol per liter] vs. 116±33 mg per deciliter[3.0±0.8 mmol per liter]); therefore, the two groupswere pooled in subsequent analyses. The distribution of plasmaLDL cholesterol levels among persons heterozygous or homozygousfor the R46L-encoding allele was shifted toward lower levels(Figure 2A), although the magnitude of the shift was smallerthan that observed with the nonsense mutations (Figure 1A).
Figure 2. Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Events (Panel B) among White Subjects, According to the Presence or Absence of a PCSK946L Allele.
In Panel A, the distribution of plasma LDL cholesterol levels at baseline among 9223 white subjects who did not have a PCSK946L allele (top) is compared with the distribution of levels among the 301 white subjects who were either heterozygous or homozygous for this allele (bottom). Panel B shows the percentage of participants from these two groups who had no evidence of coronary heart disease at baseline and in whom coronary heart disease developed during the 15-year follow-up period. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586.
Despite its more moderate LDL-lowering effect, the PCSK946Lallele was associated with a significant reduction in the incidenceof CHD (Figure 2B). Persons who were heterozygous or homozygousfor PCSK946L had a 47 percent reduction in the rate of coronaryevents (6.3 percent vs. 11.8 percent). The hazard ratio forCHD among PCSK946L carriers relative to noncarriers, after adjustmentfor age and sex, was 0.5 (95 percent confidence interval, 0.32to 0.79; P=0.003). CHD developed in only 1 of 25 blacks whowere heterozygous for the PCSK946L allele. This woman was anobese (body-mass index, 35), nondiabetic, nonhypertensive smokerwho had an LDL cholesterol level of 111 mg per deciliter (2.9mmol per liter) and an HDL cholesterol level of 27 mg per deciliter(0.7 mmol per liter). She reported no family history of heartdisease and had a myocardial infarction at the age of 53 years.
To determine whether the three PCSK9 alleles associated withlower plasma levels of LDL cholesterol were also associatedwith a reduced risk of carotid atherosclerosis, we comparedcarriers and noncarriers with respect to carotid-artery intima–mediathickness, a surrogate measure of coronary atherosclerosis.The mean intima–media thickness was slightly but significantlylower among carriers than among noncarriers, both in the groupof black subjects (Table 1) and in the group of white subjects(Table 2).
Discussion
The principal finding of this study is that sequence variationsin PCSK9 associated with lower plasma levels of LDL cholesterolconferred protection against CHD. The reduced incidence of CHDassociated with LDL-lowering PCSK9 alleles was observed in twodifferent populations. A graded association between reducedLDL cholesterol levels and a decreased risk of coronary eventswas found: the nonsense mutations that lowered plasma levelsof LDL cholesterol by about 40 mg per deciliter (1.0 mmol perliter) were associated with an 88 percent reduction in the incidenceof CHD, whereas the PCSK946L allele, which lowered LDL cholesterollevels by about 20 mg per deciliter (0.5 mmol per liter), wasassociated with a 50 percent reduction in CHD. The reductionsin CHD associated with these PCSK9 sequence variations werelarger than those predicted from LDL-lowering trials,2 presumablyreflecting the beneficial effects of lifelong reductions inplasma LDL cholesterol. These data suggest that relatively moderatereductions in LDL cholesterol level (20 to 40 mg per deciliter)would markedly reduce the incidence of CHD in the populationif sustained over a lifetime.
In several observational studies in large populations, reducedplasma levels of LDL cholesterol have been associated with reducedrates of CHD.17,18 What has not been clear from these studiesis the extent to which the risk reduction is directly attributableto lower plasma levels of LDL cholesterol and the extent towhich it is due to confounding effects from factors associatedwith LDL cholesterol levels, such as body weight, diet, medicaltherapy, or hormonal status. The identification of LDL-loweringalleles of PCSK9 that were sufficiently common allowed us tostratify subjects according to genotype and to assess the associationbetween these alleles and coronary events.
The possibility exists that the nonsense mutations and R46L-encodingallele of PCSK9 reduce CHD by a mechanism unrelated to the LDL-loweringeffect. We found no evidence that the observed association betweenthe PCSK9 nonsense mutations or R46L-encoding variant and thereduction in CHD was due to a difference in non–lipid-relatedrisk factors. Nonsense mutations in PCSK9 were not associatedwith cardiovascular risk factors (other than LDL cholesterollevel) in a prior study.4 Among black subjects in the currentstudy, hypertension was the only risk factor that was significantlyless prevalent in carriers of a PCSK9 variant than in noncarriers.Among white subjects, the prevalences of all the major cardiovascularrisk factors, including hypertension, were similar in carriersand noncarriers. These data are consistent with the notion thatreductions in the incidence of CHD associated with sequencevariations in PCSK9 are related to LDL-lowering effects. Nonetheless,PCSK9 may also have direct atherogenic effects that are independentof plasma levels of LDL cholesterol.
Anecdotal observations of atherosclerotic disease in personswith heterozygous familial hypobetalipoproteinemia have raisedthe possibility that low plasma levels of LDL cholesterol maynot prevent cardiovascular disease in the presence of othercardiovascular risk factors.19 In the current study, nonsensemutations in PCSK9 were associated with an 88 percent reductionin incident CHD among black subjects, despite the very highprevalence of non–lipid-related cardiovascular risk factorsin this population. More than one half of the black participantsin the ARIC study had hypertension, almost one third smoked,and nearly 20 percent had diabetes. The significant reductionin the incidence of CHD among black subjects with the nonsensemutations suggests that a lifelong history of reduced LDL cholesterollevels significantly lowers the risk of CHD, even in the presenceof multiple risk factors.
Several studies have estimated the potential effect of cholesterol-loweringinterventions on the burden of CHD in the population. A recentmeta-analysis of 58 trials indicated that an LDL cholesterolreduction of 38.7 mg per deciliter (1.0 mmol per liter) reducesthe risk of coronary events by 36 percent after five years.2Similar estimates were obtained from an analysis of the 10 largestcohort studies of plasma cholesterol and CHD.2 The decreasein LDL cholesterol levels in those studies is similar to thereduction associated with the two nonsense mutations in PCSK9(37 mg per deciliter [1.0 mmol per liter]), but in the currentstudy the corresponding reduction in CHD was substantially larger(88 percent). Even the more moderate reduction in LDL cholesterollevels associated with the PCSK946L allele (about 20 mg perdeciliter) was associated with a reduction in CHD (47 percent)that is similar to that achieved in statin trials (36 percent).2Adjustment according to the plasma LDL cholesterol level didnot substantially alter the hazard ratio for CHD among personswith the nonsense mutations (from 0.11 to 0.15) or with theR46L-encoding sequence variation (from 0.50 to 0.60). This resultsuggests that a single measurement of plasma LDL cholesteroldoes not capture the effect of a lifetime of reduced plasmalevels. These data suggest that lifelong reduction of LDL levelsconfers greater benefit than does a similar reduction institutedlater in life. This finding is consistent with the observationthat coronary atherosclerosis develops early in life20,21,22,23and suggests that earlier introduction of an intervention thatlowers lipid levels even moderately may confer increased protectionfrom CHD.24
The participants described in the current report were 45 to64 years old at the inception of the study and were followedfor an average of 15 years. The study does not address whetherthe cardioprotective effects of the LDL-lowering PCSK9 sequencevariations persist in older age groups. The difference betweencarriers and noncarriers in the incidence of heart disease maydecline with aging, as the absolute rates of disease increase.Moreover, it is not known whether the beneficial effect of decreasedLDL cholesterol levels on cardiovascular disease results inan overall reduction in mortality rates. The number of deathsobserved during the follow-up period was slightly lower amongcarriers than among noncarriers both in black subjects and inwhite subjects, but the difference did not reach statisticalsignificance. Further investigation in the ARIC study populationsand in cohorts of elderly persons will be required to answerthese questions.
Statins are the cornerstone of cholesterol-lowering therapyfor the prevention of CHD. Recent clinical trials have shownthat the reduction in the rate of coronary events is directlyrelated to the magnitude of the reduction in LDL cholesterollevels.2 Ironically, statin treatment increases the expressionof both the LDL-receptor gene (LDLR) and PCSK9.25 The increasedexpression of PCSK9 may attenuate the LDL-lowering effect ofstatins. Observations in genetically modified mice suggest thatinhibition of PCSK9 activity would enhance the LDL-loweringeffects of statins.11 These findings, together with the resultsof the current study, make PCSK9 an attractive new target forLDL-lowering therapy.
Supported by the Donald W. Reynolds Foundation, the W.M. KeckFoundation, and the Le Ducq Foundation; by a grant (HL 20948)from the National Institutes of Health; and as a collaborativestudy by contracts (N01-HC-55015, N01-HC-55016, N01-HC-55018,N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022)with the National Heart, Lung, and Blood Institute.
No potential conflict of interest relevant to this article wasreported.
We are indebted to the staff and participants of the ARIC studyfor their important contributions and to Michael Brown, JosephGoldstein, Scott Grundy, James DeLemos, and Darren McGuire forhelpful discussions.
Source Information
From the Donald W. Reynolds Cardiovascular Clinical Research Center (J.C.C., H.H.H.), the Center for Human Nutrition (J.C.C.), the Departments of Internal Medicine (J.C.C., H.H.H.) and Molecular Genetics (H.H.H.), and the Howard Hughes Medical Institute (H.H.H.), University of Texas Southwestern Medical Center, Dallas; the Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); and the Department of Medicine, University of Mississippi Medical Center, Jackson (T.H.M.).
Address reprint requests to Dr. Hobbs at the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas TX 75390-9046, or at helen.hobbs{at}utsouthwestern.edu.
References
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002;106:3143-3421. [Free Full Text]
Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-1427. [Free Full Text]
Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000;284:311-318. [Free Full Text]
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005;37:161-165. [Erratum, Nat Genet 2005;37:328.] [CrossRef][Web of Science][Medline]
Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 2006;78:410-422. [CrossRef][Web of Science][Medline]
Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003;100:928-933. [Free Full Text]
Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 2004;101:7100-7105. [Free Full Text]
Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004;279:50630-50638. [Free Full Text]
Lalanne F, Lambert G, Amar MJ, et al. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 2005;46:1312-1319. [Free Full Text]
Benjannet S, Rhainds D, Essalmani R, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 2004;279:48865-48875. [Free Full Text]
Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 2005;102:5374-5379. [Free Full Text]
The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol 1989;129:687-702. [Free Full Text]
Chambless LE, Folsom AR, Sharrett AR, et al. Coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. J Clin Epidemiol 2003;56:880-890. [CrossRef][Web of Science][Medline]
Brown SA, Hutchinson R, Morrisett J, et al. Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb 1993;13:1139-1158. [Free Full Text]
ARIC manual of operations. No. 2. Cohort component procedures. Chapel Hill: University of North Carolina, ARIC Coordinating Center, School of Public Health, 1987.
Bond MD, Bernes RW, Wilmoth SK, Chambless LE. High-resolution B-mode ultrasound scanning methods in the Atherosclerosis Risk in Communities Study (ARIC). J Neuroimaging 1991;1:68-73. [Medline]
Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:2823-2828. [Free Full Text]
Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ 1991;303:276-282. [Free Full Text]
Welty FK, Ordovas J, Schaefer EJ, Wilson PW, Young SG. Identification and molecular analysis of two apoB gene mutations causing low plasma cholesterol levels. Circulation 1995;92:2036-2040. [Free Full Text]
Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999;354:1234-1241. [CrossRef][Web of Science][Medline]
McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young: Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Am J Cardiol 1998;82:30T-36T. [Web of Science][Medline]
Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea; preliminary report. JAMA 1953;152:1090-1093. [Free Full Text]
McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery disease in combat casualties in Vietnam. JAMA 1971;216:1185-1187. [Free Full Text]
McGill HC Jr, McMahan CA. Starting earlier to prevent heart disease. JAMA 2003;290:2320-2322. [Free Full Text]
Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004;24:1454-1459. [Free Full Text]
Frayling, T. M
(2009). Commentary: A new dawn for genetic epidemiology?. Int J Epidemiol
0: dyp228v1-dyp228
[Full Text]
Lakoski, S. G., Lagace, T. A., Cohen, J. C., Horton, J. D., Hobbs, H. H.
(2009). Genetic and Metabolic Determinants of Plasma PCSK9 Levels. J. Clin. Endocrinol. Metab.
94: 2537-2543
[Abstract][Full Text]
Chan, J. C. Y., Piper, D. E., Cao, Q., Liu, D., King, C., Wang, W., Tang, J., Liu, Q., Higbee, J., Xia, Z., Di, Y., Shetterly, S., Arimura, Z., Salomonis, H., Romanow, W. G., Thibault, S. T., Zhang, R., Cao, P., Yang, X.-P., Yu, T., Lu, M., Retter, M. W., Kwon, G., Henne, K., Pan, O., Tsai, M.-M., Fuchslocher, B., Yang, E., Zhou, L., Lee, K. J., Daris, M., Sheng, J., Wang, Y., Shen, W. D., Yeh, W.-C., Emery, M., Walker, N. P. C., Shan, B., Schwarz, M., Jackson, S. M.
(2009). From the Cover: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl. Acad. Sci. USA
106: 9820-9825
[Abstract][Full Text]
Steinberg, D., Witztum, J. L.
(2009). Inhibition of PCSK9: A powerful weapon for achieving ideal LDL cholesterol levels. Proc. Natl. Acad. Sci. USA
106: 9546-9547
[Full Text]
Drenos, F., Talmud, P. J., Casas, J. P., Smeeth, L., Palmen, J., Humphries, S. E., Hingorani, A. D.
(2009). Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk. Hum Mol Genet
18: 2305-2316
[Abstract][Full Text]
Thanassoulis, G., O'Donnell, C. J.
(2009). Mendelian Randomization: Nature's Randomized Trial in the Post-Genome Era. JAMA
301: 2386-2388
[Full Text]
Keebler, M. E., Sanders, C. L., Surti, A., Guiducci, C., Burtt, N. P., Kathiresan, S.
(2009). Association of Blood Lipids With Common DNA Sequence Variants at 19 Genetic Loci in the Multiethnic United States National Health and Nutrition Examination Survey III. Circ Cardiovasc Genet
2: 238-243
[Abstract][Full Text]
Le May, C., Kourimate, S., Langhi, C., Chetiveaux, M., Jarry, A., Comera, C., Collet, X., Kuipers, F., Krempf, M., Cariou, B., Costet, P.
(2009). Proprotein Convertase Subtilisin Kexin Type 9 Null Mice Are Protected From Postprandial Triglyceridemia. Arterioscler. Thromb. Vasc. Bio.
29: 684-690
[Abstract][Full Text]
McNutt, M. C., Kwon, H. J., Chen, C., Chen, J. R., Horton, J. D., Lagace, T. A.
(2009). Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells. J. Biol. Chem.
284: 10561-10570
[Abstract][Full Text]
Fazio, S., Linton, M. F.
(2009). Elevated High-Density Lipoprotein (HDL) Levels due to Hepatic Lipase Mutations Do Not Reduce Cardiovascular Disease Risk: Another Strike against the HDL Dogma. J. Clin. Endocrinol. Metab.
94: 1081-1083
[Full Text]
Minhas, R, Humphries, S E, Qureshi, N, Neil, H A W, on behalf of the NICE Guideline Development Group,
(2009). Controversies in familial hypercholesterolaemia: recommendations of the NICE Guideline Development Group for the identification and management of familial hypercholesterolaemia. Heart
95: 584-587
[Full Text]
Karalis, D. G.
(2009). Intensive Lowering of Low-Density Lipoprotein Cholesterol Levels for Primary Prevention of Coronary Artery Disease. Mayo Clin Proc.
84: 345-352
[Abstract][Full Text]
Plump, A. S., Lum, P. Y.
(2009). Genomics and cardiovascular drug development.. J Am Coll Cardiol
53: 1089-1100
[Abstract][Full Text]
Tai, E. S., Sim, X. L., Ong, T. H., Wong, T. Y., Saw, S. M., Aung, T., Kathiresan, S., Orho-Melander, M., Ordovas, J. M., Tan, J. T., Seielstad, M.
(2009). Polymorphisms at newly identified lipid-associated loci are associated with blood lipids and cardiovascular disease in an Asian Malay population. J. Lipid Res.
50: 514-520
[Abstract][Full Text]
Kao, W.H. L., Arking, D. E., Post, W., Rea, T. D., Sotoodehnia, N., Prineas, R. J., Bishe, B., Doan, B. Q., Boerwinkle, E., Psaty, B. M., Tomaselli, G. F., Coresh, J., Siscovick, D. S., Marban, E., Spooner, P. M., Burke, G. L., Chakravarti, A.
(2009). Genetic Variations in Nitric Oxide Synthase 1 Adaptor Protein Are Associated With Sudden Cardiac Death in US White Community-Based Populations. Circulation
119: 940-951
[Abstract][Full Text]
McPherson, R.
(2009). A Gene-Centric Approach to Elucidating Cardiovascular Risk. Circ Cardiovasc Genet
2: 3-6
[Full Text]
Ridker, P. M., Pare, G., Parker, A. N., Zee, R. Y.L., Miletich, J. P., Chasman, D. I.
(2009). Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction: Genomewide Analysis Among 18 245 Initially Healthy Women From the Women's Genome Health Study. Circ Cardiovasc Genet
2: 26-33
[Abstract][Full Text]
Bottomley, M. J., Cirillo, A., Orsatti, L., Ruggeri, L., Fisher, T. S., Santoro, J. C., Cummings, R. T., Cubbon, R. M., Lo Surdo, P., Calzetta, A., Noto, A., Baysarowich, J., Mattu, M., Talamo, F., De Francesco, R., Sparrow, C. P., Sitlani, A., Carfi, A.
(2009). Structural and Biochemical Characterization of the Wild Type PCSK9-EGF(AB) Complex and Natural Familial Hypercholesterolemia Mutants. J. Biol. Chem.
284: 1313-1323
[Abstract][Full Text]
Chasman, D. I., Pare, G., Ridker, P. M
(2009). Population-Based Genomewide Genetic Analysis of Common Clinical Chemistry Analytes. Clin. Chem.
55: 39-51
[Abstract][Full Text]
Pollin, T. I., Damcott, C. M., Shen, H., Ott, S. H., Shelton, J., Horenstein, R. B., Post, W., McLenithan, J. C., Bielak, L. F., Peyser, P. A., Mitchell, B. D., Miller, M., O'Connell, J. R., Shuldiner, A. R.
(2008). A Null Mutation in Human APOC3 Confers a Favorable Plasma Lipid Profile and Apparent Cardioprotection. Science
322: 1702-1705
[Abstract][Full Text]
Mukherjee, R., Locke, K. T., Miao, B., Meyers, D., Monshizadegan, H., Zhang, R., Search, D., Grimm, D., Flynn, M., O'Malley, K. M., Zhang, L., Li, J., Shi, Y., Kennedy, L. J., Blanar, M., Cheng, P. T., Tino, J., Srivastava, R. A.
(2008). Novel Peroxisome Proliferator-Activated Receptor {alpha} Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist. J. Pharmacol. Exp. Ther.
327: 716-726
[Abstract][Full Text]
Abifadel, M, Bernier, L, Dubuc, G, Nuel, G, Rabes, J-P, Bonneau, J, Marques, A, Marduel, M, Devillers, M, Munnich, A, Erlich, D, Varret, M, Roy, M, Davignon, J, Boileau, C
(2008). A PCSK9 variant and familial combined hyperlipidaemia. J. Med. Genet.
45: 780-786
[Abstract][Full Text]
Mayer, G., Poirier, S., Seidah, N. G.
(2008). Annexin A2 Is a C-terminal PCSK9-binding Protein That Regulates Endogenous Low Density Lipoprotein Receptor Levels. J. Biol. Chem.
283: 31791-31801
[Abstract][Full Text]
Altshuler, D., Daly, M. J., Lander, E. S.
(2008). Genetic Mapping in Human Disease. Science
322: 881-888
[Abstract][Full Text]
Neil, A., Cooper, J., Betteridge, J., Capps, N., McDowell, I., Durrington, P., Seed, M., Humphries, S. E., on behalf of the Simon Broome Familial Hyperlipida,
(2008). Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J
29: 2625-2633
[Abstract][Full Text]
McCarroll, S. A.
(2008). Extending genome-wide association studies to copy-number variation. Hum Mol Genet
17: R135-R142
[Abstract][Full Text]
O'Donnell, C. J., Nabel, E. G.
(2008). Cardiovascular Genomics, Personalized Medicine, and the National Heart, Lung, and Blood Institute: Part I: The Beginning of an Era. Circ Cardiovasc Genet
1: 51-57
[Full Text]
Blesa, S., Vernia, S., Garcia-Garcia, A.-B., Martinez-Hervas, S., Ivorra, C., Gonzalez-Albert, V., Ascaso, J. F., Martin-Escudero, J. C., Real, J. T., Carmena, R., Casado, M., Chaves, F. J.
(2008). A New PCSK9 Gene Promoter Variant Affects Gene Expression and Causes Autosomal Dominant Hypercholesterolemia. J. Clin. Endocrinol. Metab.
93: 3577-3583
[Abstract][Full Text]
Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N., Orkin, S. H.
(2008). From the Cover: DNA polymorphisms at the BCL11A, HBS1L-MYB, and {beta}-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc. Natl. Acad. Sci. USA
105: 11869-11874
[Abstract][Full Text]
Frank-Kamenetsky, M., Grefhorst, A., Anderson, N. N., Racie, T. S., Bramlage, B., Akinc, A., Butler, D., Charisse, K., Dorkin, R., Fan, Y., Gamba-Vitalo, C., Hadwiger, P., Jayaraman, M., John, M., Jayaprakash, K. N., Maier, M., Nechev, L., Rajeev, K. G., Read, T., Rohl, I., Soutschek, J., Tan, P., Wong, J., Wang, G., Zimmermann, T., de Fougerolles, A., Vornlocher, H.-P., Langer, R., Anderson, D. G., Manoharan, M., Koteliansky, V., Horton, J. D., Fitzgerald, K.
(2008). Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA
105: 11915-11920
[Abstract][Full Text]
Steinberg, D., Glass, C. K., Witztum, J. L.
(2008). Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia. Circulation
118: 672-677
[Full Text]
Peterson, A. S., Fong, L. G., Young, S. G.
(2008). Errata. PCSK9 function and physiology. J. Lipid Res.
49: 1595-1599
[Abstract][Full Text]
Grefhorst, A., McNutt, M. C., Lagace, T. A., Horton, J. D.
(2008). Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res.
49: 1303-1311
[Abstract][Full Text]
Peterson, A. S., Fong, L. G., Young, S. G.
(2008). PCSK9 function and physiology. J. Lipid Res.
49: 1152-1156
[Full Text]
Kathiresan, S., the Myocardial Infarction Genetics Consortium,
(2008). A PCSK9 Missense Variant Associated with a Reduced Risk of Early-Onset Myocardial Infarction. NEJM
358: 2299-2300
[Full Text]
Brunzell, J. D., Davidson, M., Furberg, C. D., Goldberg, R. B., Howard, B. V., Stein, J. H., Witztum, J. L.
(2008). Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol
51: 1512-1524
[Full Text]
Kourimate, S., Le May, C., Langhi, C., Jarnoux, A. L., Ouguerram, K., Zair, Y., Nguyen, P., Krempf, M., Cariou, B., Costet, P.
(2008). Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9. J. Biol. Chem.
283: 9666-9673
[Abstract][Full Text]
Brunzell, J. D., Davidson, M., Furberg, C. D., Goldberg, R. B., Howard, B. V., Stein, J. H., Witztum, J. L.
(2008). Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care
31: 811-822
[Full Text]
Krauss, R. M., Mangravite, L. M., Smith, J. D., Medina, M. W., Wang, D., Guo, X., Rieder, M. J., Simon, J. A., Hulley, S. B., Waters, D., Saad, M., Williams, P. T., Taylor, K. D., Yang, H., Nickerson, D. A., Rotter, J. I.
(2008). Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment. Circulation
117: 1537-1544
[Abstract][Full Text]
Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M.
(2008). Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events. NEJM
358: 1240-1249
[Abstract][Full Text]
McGill, H. C. Jr, McMahan, C. A., Gidding, S. S.
(2008). Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study. Circulation
117: 1216-1227
[Full Text]
Grundy, S. M.
(2008). A changing paradigm for prevention of cardiovascular disease: emergence of the metabolic syndrome as a multiplex risk factor. Eur Heart J Suppl
10: B16-B23
[Abstract][Full Text]
Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J.
(2008). Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA
105: 1820-1825
[Abstract][Full Text]
Andon, M. B., Anderson, J. W.
(2008). State of the Art Reviews: The Oatmeal-Cholesterol Connection: 10 Years Later. AMERICAN JOURNAL OF LIFESTYLE MEDICINE
2: 51-57
[Abstract]
Jeong, H. J., Lee, H.-S., Kim, K.-S., Kim, Y.-K., Yoon, D., Park, S. W.
(2008). Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res.
49: 399-409
[Abstract][Full Text]
Careskey, H. E., Davis, R. A., Alborn, W. E., Troutt, J. S., Cao, G., Konrad, R. J.
(2008). Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res.
49: 394-398
[Abstract][Full Text]
Iakoubova, O. A., Sabatine, M. S., Rowland, C. M., Tong, C. H., Catanese, J. J., Ranade, K., Simonsen, K. L., Kirchgessner, T. G., Cannon, C. P., Devlin, J. J., Braunwald, E.
(2008). Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study.. J Am Coll Cardiol
51: 449-455
[Abstract][Full Text]
Grundy, S. M.
(2008). Promise of Low-Density Lipoprotein-Lowering Therapy for Primary and Secondary Prevention. Circulation
117: 569-573
[Full Text]
Grundy, S. M.
(2008). Thyroid mimetic as an option for lowering low-density lipoprotein. Proc. Natl. Acad. Sci. USA
105: 409-410
[Full Text]
Damani, S. B., Topol, E. J.
(2007). Future Use of Genomics in Coronary Artery Disease. J Am Coll Cardiol
50: 1933-1940
[Abstract][Full Text]
Folsom, A. R., Peacock, J. M., Boerwinkle, E.
(2007). Sequence Variation in Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease Gene, Low LDL Cholesterol, and Cancer Incidence. Cancer Epidemiol. Biomarkers Prev.
16: 2455-2458
[Abstract][Full Text]
Tabas, I., Williams, K. J., Boren, J.
(2007). Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications. Circulation
116: 1832-1844
[Abstract][Full Text]
Domanski, M. J.
(2007). Primary Prevention of Coronary Artery Disease. NEJM
357: 1543-1545
[Full Text]
Cambien, F., Tiret, L.
(2007). Genetics of Cardiovascular Diseases: From Single Mutations to the Whole Genome. Circulation
116: 1714-1724
[Full Text]
Alborn, W. E., Cao, G., Careskey, H. E., Qian, Y.-W., Subramaniam, D. R., Davies, J., Conner, E. M., Konrad, R. J.
(2007). Serum Proprotein Convertase Subtilisin Kexin Type 9 Is Correlated Directly with Serum LDL Cholesterol. Clin. Chem.
53: 1814-1819
[Abstract][Full Text]
Hampton, E. N., Knuth, M. W., Li, J., Harris, J. L., Lesley, S. A., Spraggon, G.
(2007). The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc. Natl. Acad. Sci. USA
104: 14604-14609
[Abstract][Full Text]
Galman, C., Matasconi, M., Persson, L., Parini, P., Angelin, B., Rudling, M.
(2007). Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol. Am. J. Physiol. Endocrinol. Metab.
293: E737-E742
[Abstract][Full Text]
Arnett, D. K., for the Writing Group,
(2007). Summary of the American Heart Association's Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease. Arterioscler. Thromb. Vasc. Bio.
27: 1682-1686
[Full Text]
McNutt, M. C., Lagace, T. A., Horton, J. D.
(2007). Catalytic Activity Is Not Required for Secreted PCSK9 to Reduce Low Density Lipoprotein Receptors in HepG2 Cells. J. Biol. Chem.
282: 20799-20803
[Abstract][Full Text]
Fisher, T. S., Surdo, P. L., Pandit, S., Mattu, M., Santoro, J. C., Wisniewski, D., Cummings, R. T., Calzetta, A., Cubbon, R. M., Fischer, P. A., Tarachandani, A., De Francesco, R., Wright, S. D., Sparrow, C. P., Carfi, A., Sitlani, A.
(2007). Effects of pH and Low Density Lipoprotein (LDL) on PCSK9-dependent LDL Receptor Regulation. J. Biol. Chem.
282: 20502-20512
[Abstract][Full Text]
Qian, Y.-W., Schmidt, R. J., Zhang, Y., Chu, S., Lin, A., Wang, H., Wang, X., Beyer, T. P., Bensch, W. R., Li, W., Ehsani, M. E., Lu, D., Konrad, R. J., Eacho, P. I., Moller, D. E., Karathanasis, S. K., Cao, G.
(2007). Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res.
48: 1488-1498
[Abstract][Full Text]
Arnett, D. K., Baird, A. E., Barkley, R. A., Basson, C. T., Boerwinkle, E., Ganesh, S. K., Herrington, D. M., Hong, Y., Jaquish, C., McDermott, D. A., O'Donnell, C. J.
(2007). Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation
115: 2878-2901
[Abstract][Full Text]
Windler, E., Schoffauer, M., Zyriax, B.-C.
(2007). The significance of low HDL-cholesterol levels in an ageing society at increased risk for cardiovascular disease. Diabetes and Vascular Disease Research
4: 136-142
[Abstract]
Horne, B. D., Camp, N. J., Anderson, J. L., Mower, C. P., Clarke, J. L., Kolek, M. J., Carlquist, J. F., for the Intermountain Heart Collaborative Study Gr,
(2007). Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease. J Am Coll Cardiol
49: 2053-2060
[Abstract][Full Text]
Garg, A., Simha, V.
(2007). Update on Dyslipidemia. J. Clin. Endocrinol. Metab.
92: 1581-1589
[Abstract][Full Text]
Ntzani, E. E., Rizos, E. C., Ioannidis, J. P. A.
(2007). Genetic Effects versus Bias for Candidate Polymorphisms in Myocardial Infarction: Case Study and Overview of Large-Scale Evidence. Am J Epidemiol
165: 973-984
[Abstract][Full Text]
Miller, D. T., Ridker, P. M., Libby, P., Kwiatkowski, D. J.
(2007). Atherosclerosis: The Path From Genomics to Therapeutics. J Am Coll Cardiol
49: 1589-1599
[Abstract][Full Text]
Deanfield, J. E., Halcox, J. P., Rabelink, T. J.
(2007). Endothelial Function and Dysfunction: Testing and Clinical Relevance. Circulation
115: 1285-1295
[Full Text]
Fasano, T., Cefalu, A. B., Di Leo, E., Noto, D., Pollaccia, D., Bocchi, L., Valenti, V., Bonardi, R., Guardamagna, O., Averna, M., Tarugi, P.
(2007). A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol. Arterioscler. Thromb. Vasc. Bio.
27: 677-681
[Abstract][Full Text]
Anwaruddin, S., Askari, A. T., Topol, E. J.
(2007). Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine. J Am Coll Cardiol
49: 279-289
[Abstract][Full Text]
Lange, L. A., Carlson, C. S., Hindorff, L. A., Lange, E. M., Walston, J., Durda, J. P., Cushman, M., Bis, J. C., Zeng, D., Lin, D., Kuller, L. H., Nickerson, D. A., Psaty, B. M., Tracy, R. P., Reiner, A. P.
(2006). Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events. JAMA
296: 2703-2711
[Abstract][Full Text]
Waxman, S., Ishibashi, F., Muller, J. E.
(2006). Detection and Treatment of Vulnerable Plaques and Vulnerable Patients: Novel Approaches to Prevention of Coronary Events. Circulation
114: 2390-2411
[Full Text]
Gidding, S. S., McMahan, C. A., McGill, H. C., Colangelo, L. A., Schreiner, P. J., Williams, O. D., Liu, K.
(2006). Prediction of Coronary Artery Calcium in Young Adults Using the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Risk Score: The CARDIA Study. Arch Intern Med
166: 2341-2347
[Abstract][Full Text]
Topol, E. J., Smith, J., Plow, E. F., Wang, Q. K.
(2006). Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet
15: R117-R123
[Abstract][Full Text]
Lambert, G., Jarnoux, A.-L., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., Costet, P.
(2006). Fasting Induces Hyperlipidemia in Mice Overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of Modulation of Very-Low-Density Lipoprotein Hepatic Output by the Low-Density Lipoprotein Receptor. Endocrinology
147: 4985-4995
[Abstract][Full Text]
Parhofer, K. G., Barrett, P. H. R.
(2006). Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies. J. Lipid Res.
47: 1620-1630
[Abstract][Full Text]
(2006). Variations in Low-LDL Gene Linked with Reduced CHD Risk. Journal Watch Cardiology
2006: 3-3
[Full Text]
Tall, A. R.
(2006). Protease variants, LDL, and coronary heart disease.. NEJM
354: 1310-1312
[Full Text]
G, encoding Y142X [replacement of the tyrosine at position 142 with a stop codon], and 2037C
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