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Original Investigation |

Lipoprotein(a) Levels and Risk of Future Coronary Heart Disease:  Large-Scale Prospective Data FREE

Anna Bennet, PhD; Emanuele Di Angelantonio, MD, MSc; Sebhat Erqou, MD, MPhil; Gudny Eiriksdottir, MSc; Gunnar Sigurdsson, MD, PhD; Mark Woodward, PhD; Ann Rumley, PhD; Gordon D. O. Lowe, MD, FRCP; John Danesh, FRCP, DPhil; Vilmundur Gudnason, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Drs Bennet, Di Angelantonio, Erqou, and Danesh); Icelandic Heart Association, Kopavogur, Iceland (Ms Eiriksdottir and Drs Sigurdsson and Gudnason); University of Iceland, Reykjavik (Drs Sigurdsson and Gudnason); Department of Medicine, Mount Sinai Medical Center, New York, New York (Dr Woodward); and Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland (Drs Rumley and Lowe).


Arch Intern Med. 2008;168(6):598-608. doi:10.1001/archinte.168.6.598.
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Published online

Background  Large-scale prospective data are needed to determine whether associations between lipoprotein(a) (Lp[a]) and coronary heart disease (CHD) risk are independent of established risk factors, to characterize the shape of this relationship, and to quantify associations in relevant subgroups.

Methods  Levels of Lp(a) were measured in samples obtained at baseline from 2047 patients who had first-ever nonfatal myocardial infarction or who died of CHD during the study and from 3921 control participants in the Reykjavik Study (n = 18 569), as well as in paired samples obtained 12 years apart from 372 participants to quantify within-person fluctuations.

Results  Baseline Lp(a) levels had little or no correlation with known cardiovascular risk factors, such as age, sex, total cholesterol level, and blood pressure. The Lp(a) values were highly consistent from decade to decade, with a regression dilution ratio (calculated on the log scale) of 0.92 (95% confidence interval, 0.85-0.99). The odds ratio for CHD, unaltered after adjustment for several established risk factors (age, sex, smoking status, blood pressure, total cholesterol, triglycerides level, diabetes mellitus, and body mass index), was 1.60 (95% confidence interval, 1.38-1.85) in a comparison of extreme thirds of baseline Lp(a) levels. Odds ratios were progressively higher with increasing Lp(a) levels and did not vary materially by several individual- or study-level characteristics.

Conclusions  There are independent, continuous associations between Lp(a) levels and risk of future CHD in a broad range of individuals. Levels of Lp(a) are highly stable within individuals across many years and are only weakly correlated with known risk factors. Further assessment of their possible role in CHD prevention is warranted.

Figures in this Article

Lipoprotein(a) (Lp[a]) is a low-density lipoprotein–like particle synthesized by the liver that consists of an apolipoprotein B molecule covalently linked to a very large glycoprotein known as apolipoprotein(a) (Apo[a]).1,2 Several epidemiologic studies have assessed the association between circulating Lp(a) levels and cardiovascular diseases. By 2000, there were 18 population-based prospective studies320 that had reported on Lp(a) levels and coronary heart disease (CHD) risk, with most, but not all, reporting positive associations. Few studies, however, have been adequately powered to examine potentially important aspects of the association, such as the shape of the Lp(a)-CHD relationship and the size of relative risks in clinically relevant subgroups (such as in men and women or at different levels of established risk factors). A previous review21 suggested a moderately strong overall association between Lp(a) levels and CHD risk, but because it analyzed only published data (rather than primary data) it did not address the uncertainties described in the preceding sentences. Furthermore, data on within-person variability are needed to help assess the long-term relevance of Lp(a) to CHD, but only 1 previous study22 has reported on it using a small subset of individuals.

We report new primary data on the largest single study of Lp(a) concentrations and CHD thus far, involving 2047 patients with either first-ever nonfatal myocardial infarction or coronary death and 3921 control subjects “nested” within a prospective population-based cohort of 18 569 participants. As recommended by an expert panel,23 we used an assay system that is not sensitive to Apo(a) isoform heterogeneity. Paired measurements were performed approximately 12 years apart in 372 participants to help quantify within-person variability in Lp(a) levels. We also report an updated review of previous prospective studies to help assess the comparability of associations of Lp(a) level with CHD risk reported in studies involving different blood handling, storage, and assay methods, particularly with assays affected by the variable affinity of antibodies to particular Apo(a) isoforms.24,25 The focus of the present report is on whether there is likely to be an etiologic association between Lp(a) levels and CHD (rather than the separate issue of risk prediction).

STUDY POPULATION

The Reykjavik Study, initiated in 1967, has been described in detail elsewhere.26 All men born between January 1, 1907, and December 31, 1934, and all women born between January 1, 1908, and December 31, 1935, who were residents of Reykjavik and its adjacent communities on December 1, 1966, were identified in the national population register and were invited to participate in the study. Five stages of recruitment, between 1967 and 1991, yielded 8888 male and 9681 female participants with no history of myocardial infarction (72% response rate). Nurses administered questionnaires, performed physical measurements, recorded electrocardiograms, and collected fasting venous blood samples. Serum was stored at −20°C until assay. All the participants were monitored by central registries for the occurrence of major cardiovascular morbidity (based on MONICA [Monitoring Trends and Determinants in Cardiovascular Disease] criteria) or cause-specific mortality (based on a death certificate with International Classification of Diseases, Ninth Revision codes 410-414), with loss to follow-up of only approximately 0.6% to date. A total of 2459 men and women recorded either nonfatal myocardial infarction or coronary death between study entry and the censoring date. One or 2 controls were frequency matched to cases by calendar year of recruitment, sex, and age (in 5-year age bands) from among all participants who did not develop CHD during follow-up, giving a total of 3969 controls. Because of random nonavailability of serum samples, the present study is restricted to 2418 incident CHD cases and 3921 controls with available Lp(a) measurements. The study protocol was approved by the National Bioethics Committee and the Data Protection Commission of Iceland. All the participants gave informed consent.

LABORATORY METHODS

Levels of Lp(a) were measured in serum samples by laboratory staff unaware of participants' disease status using an enzyme immunoassay (ELITEST Lp[a]) and an assay standard (both from HYPHEN BioMed, Paris, France). This enzyme-linked immunosorbent assay–based system, which uses a monoclonal anti-Lp(a) antibody for capture and a polyclonal anti-Apo(B) antibody for detection, is not affected by Apo(a) isoform variation. The intra-assay and interassay coefficients of variation were 4.2% and 4.7%, respectively. The Lp(a) measurements were made in the 372 participants who provided paired samples at a mean interval of approximately 12 years. Lipid, biochemical, and hematologic measurements have been described previously.26,27

STATISTICAL ANALYSES

To minimize any impact of preexisting disease, principal analyses were restricted to the 2047 patients and 3921 controls without evidence of CHD or stroke at the baseline examination (ie, participants with electrocardiographic abnormalities or a history of myocardial infarction, angina, or stroke were excluded from the main analyses, although they were retained in subsidiary analyses). The Lp(a) values were natural log transformed to achieve an approximately symmetrical distribution. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), progressively adjusted for possible confounding factors (Stata 9.2;StataCorp LP, College Station, Texas). The shape of the association between Lp(a) levels and CHD risk was investigated using groups defined by fifths of the baseline values of Lp(a) in controls; the corresponding 95% CIs were estimated from floated variances that reflect the amount of information underlying each group (including the reference group).28 Subgroup analyses by sex, smoking habits, systolic and diastolic blood pressure (BP), concentrations of serum lipids and C-reactive protein, and type of CHD outcome were also prespecified. To quantify within-person variability in levels of Lp(a) (and in other markers), regression dilution ratios were estimated from the available paired measurements by regressing repeated measures on baseline values. Regression dilution ratios for variables with skewed distributions (ie, Lp[a], C-reactive protein, and triglycerides) were calculated on the log scale.29 An updated meta-analysis was conducted of prospective studies published before December 1, 2006, with more than 1 year of follow-up in essentially general populations (ie, in cohorts not selected on the basis of preexisting disease).30 The analysis was restricted to nonfatal myocardial infarction or coronary death. To reduce potential biases, all the analyses involved only within-study comparisons (ie, cases and controls were directly compared only within each cohort). Data were combined using a random-effects model. Heterogeneity was assessed using standard χ2 tests and the I2 statistic.31 In the few studies that reported only 3 or 4 categories of Lp(a), rather than continuous values (owing to the use of semiquantitative assays based on reading of electrophoretic bands6,11), the highest category was taken to correspond to the upper third and the lowest category to the bottom third of baseline Lp(a) values. For studies reporting associations for men and women separately, a pooled estimate was calculated, weighted by their contributing proportions. Analyses involved formal tests of interaction to assess the effect of the following prespecified study characteristics: year of publication, study size, geographic location, ethnicity, sample storage features (ie, temperature and type), and features related to Lp(a) assay methods used.

As expected, levels of established cardiovascular risk factors at the baseline examination were higher in patients with CHD than in controls (Table 1). Baseline log-Lp(a) levels were higher in patients with CHD than in controls and were weakly, although significantly, correlated with levels of total cholesterol (r = 0.12; 95% CI, 0.09 to 0.15), log triglycerides (r = −0.12; 95% CI, −0.16 to −0.09), tissue plasminogen activator antigen (r = −0.09; 95% CI, −0.12 to −0.06), serum creatinine (r = −0.05; 95% CI, −0.08 to −0.02), and uric acid (r = −0.06; 95% CI, −0.09 to −0.02). There were no significant correlations between baseline log-Lp(a) levels and various established and emerging cardiovascular risk factors, such as age, sex, BP, body mass index, C-reactive protein, and albumin (data available on request). In the 372 participants who provided paired measurements at baseline and approximately12 years later, the regression dilution ratios were as follows: 0.92 (95% CI, 0.85-0.99) for log Lp(a), 0.54 (95% CI, 0.44-0.64) for log C-reactive protein, 0.57 (95% CI, 0.48-0.66) for log triglycerides, 0.55 (95% CI, 0.45-0.65) for von Willebrand factor, 0.59 (95% CI, 0.51-0.67) for total cholesterol, and 0.65 (95% CI, 0.54-0.77) for systolic BP (Figure 1A). Data on high-density lipoprotein cholesterol were unavailable.

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Figure 1.

Direct comparisons of lipoprotein(a) values, several established cardiovascular risk factors, and emerging markers in relation to within-person variability across 12 years (expressed as the regression dilution ratio [calculated using the Rosner multivariate regression method, adjusted for baseline age, sex, smoking history, diabetes mellitus history, total cholesterol, log triglycerides, systolic blood pressure, and body mass index]) (A) and odds ratios (top third vs bottom third) for coronary heart disease (CHD) (adjusted for established risk factors [age, sex, period of recruitment, smoking status, history of diabetes mellitus, total cholesterol, log triglycerides, systolic blood pressure, and body mass index]) (B). *Regression dilution ratios were calculated using the log-transformed variables. Error bars represent 95% confidence intervals.

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Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients With Coronary Heart Disease and Controls in the Reykjavik Study

In a comparison of individuals with baseline Lp(a) values in the top third vs the bottom third, the OR for CHD was 1.61 (95% CI, 1.41-1.84) after adjustment for age, sex, and calendar year of recruitment (Table 2). This OR changed little after further adjustment for several established cardiovascular risk factors (ie, smoking status, BP, total cholesterol, triglycerides, body mass index, and diabetes mellitus) and inflammatory markers (eg, C-reactive protein). Subsidiary analyses yielded adjusted ORs for CHD of 1.77 (95% CI, 1.57-1.99) in a comparison of extreme fifths and of 1.23 (95% CI, 1.16-1.31) for log-Lp(a) levels higher by 1 SD. Figure 1B shows that, in comparisons of several established and emerging markers in the same patients and controls, ORs for CHD with Lp(a) were smaller than those with total cholesterol. Figure 2 shows that the ORs for CHD increased continuously with increasing Lp(a) levels (P < .001, test for linear trend), although further work is needed to determine whether a straight line or a curvilinear line better describes the association. Figure 3A suggests that the association of Lp(a) levels with CHD risk did not vary materially in a range of subgroups based on individual characteristics, notably, sex, lipid concentrations, C-reactive protein, and fatal vs nonfatal CHD outcome (P > .10 for each test of heterogeneity).3247

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Figure 2.

Odds ratios for coronary heart disease by fifths (F) of baseline lipoprotein(a) levels adjusted for age, sex, period of recruitment, smoking status, and other established risk factors (total cholesterol, log triglycerides, systolic blood pressure, history of diabetes mellitus, and body mass index). The size of the data markers is proportional to the inverse of the variance of the odds ratios. Fifths were calculated on the basis of the distribution of controls. Geometric mean baseline lipoprotein(a) values in each F were as follows: F1, 3.49 mg/L; F2, 35.29 mg/L; F3, 84.23 mg/L; F4, 171.30 mg/L; and F5, 383.42 mg/L (to convert to micromoles per liter, multiply by 0.0357). Test for linear trend of odds ratios across fifths of lipoprotein(a) levels: P < .001. Error bars represent 95% confidence intervals (CIs) (calculated using floating variances).

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Figure 3.

Investigation of possible sources of heterogeneity in associations between lipoprotein(a) (Lp[a]) levels and risk of coronary heart disease (CHD) involving individual characteristics in the Reykjavik Study (A) and study-level characteristics in an updated meta-analysis of 31 studies (B). Values are adjusted for age, sex, smoking status, total cholesterol (to convert to millimoles per liter, multiply by 0.0259), log triglycerides (to convert to millimoles per liter, multiply by 0.0113), systolic blood pressure, body mass index, and history of diabetes mellitus. The size of the data markers is proportional to the inverse of the variance of the odds ratios. Thirds of systolic blood pressure, total cholesterol, triglycerides, and tissue plasminogen activator antigen were defined by their respective distributions in cases. Apart from heterogeneity for publication period (P = .004) and sample type (P = .003), there was no evidence of significant interaction between the different subgroups and Lp(a) levels. Error bars represent 95% confidence intervals. To convert C-reactive protein to nanomoles per liter, multiply by 9.524.

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Table Graphic Jump LocationTable 2. Relative Odds for CHD in Participants Without Known Coronary Disease at Baselinea in a Comparison of Extreme Thirdsb of Baseline Lp(a) Levels

Table 3 and Table 4 summarize the characteristics of 31 prospective studies of Lp(a), the first of which was published in 1990,19 with 14 studies reported since the publication of a meta-analysis in 2000.3241,4346 All the studies were based in continental North America or in Western Europe except 1.36 Most studies identified participants in population registers (eg, general practitioner lists or electoral rolls) or in occupational settings, involved middle-aged men of white European continental ancestry, and reported on incident myocardial infarction and coronary death outcomes. The interval between sample collection and assay performance varied from a few hours to approximately 20 years. Eighteen studies7,8,11,14,15,17,3235,3942,44,4648 measured Lp(a) levels in plasma and 13 studies (including the present study)5,6,10,12,13,18,19,36,37,45 in serum, with measurements generally performed in samples thawed after long-term storage at temperatures of −70°C or colder, whereas few studies conducted assays in samples stored at temperatures ranging from −70°C to −20°C12,17,18,39,41 or in freshly collected samples.6,10,35 Apart from 6 studies6,8,10,11,32,35 that used in-house Lp(a) assays, most of the studies used commercially available immunoassays. Assay results were generally reported as mass per volume, although 1 study8 used an analytical method that measured molarity, and 2 studies6,11 used semiquantitative assay methods. Detailed information on assay methods (such as the exact antibodies used and the existence of sensitivity to Lp[a] isoforms) was reported in only a subset of studies (Table 4). Reported mean or median levels of Lp(a) in controls varied substantially across studies, ranging from approximately 10 to 300 mg/L (to convert to micromoles per liter, multiply by 0.0357) (although, as in the present study, most were 50-200 mg/L). All but 3 studies10,32,45 reported adjustment of CHD ORs for at least age, sex, smoking status, BP, and lipid concentrations. Using only within-study comparisons, a combined analysis of published data from these studies (including the present study) involving a total of 9870 incident CHD cases yielded an adjusted OR of 1.45 (95% CI, 1.32-1.58) for individuals in the top third of the baseline Lp(a) distribution compared with those in the bottom third (Figure 4). There was moderate heterogeneity among these studies (χ230 = 52.6; P = .007; I2 = 43% [95% CI, 12%-63%]), some of which was explained by period of publication (P = .004) and sample type (P = .003) but only a small part by other characteristics prespecified for investigation, notably, study size, sample storage characteristics, and Lp(a) assay isoform sensitivity or standard used (P > .10 for each characteristic) (Figure 3B). A funnel plot did not show an excess of extreme findings in smaller studies (Egger test P = .23) (data available on request).

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Figure 4.

Odds ratios for coronary heart disease (CHD) (top third vs bottom third) in each of 31 published prospective studies of lipoprotein(a) in essentially general populations. Heterogeneity: χ230 = 52.6; P = .007: I2 = 43% (95% confidence interval [CI], 12%-63%). ARIC indicates Atherosclerosis Risk in Communities; BUPA, British United Provident Association; GRIPS, Göttingen Risk, Incidence and Prevalence Study; Lip Res Clin Prev Trial, Lipid Research Clinics Coronary Primary Prevention Trial; MONICA, Monitoring Trends and Determinants in Cardiovascular Disease; MRFIT, Multiple Risk Factor Intervention Trial; PRIME, Prospective Epidemiological Study of Myocardial Infarction; PROCAM, Prospective Cardiovascular Münster Study; VIP, Västerbotten Intervention Project; WHS, Women's Health Study; and WOSCOPS, West of Scotland Coronary Prevention Study. Error bars represent 95% CIs.

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Table Graphic Jump LocationTable 3. Population Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations
Table Graphic Jump LocationTable 4. Laboratory Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations

We demonstrated that the decade-to-decade consistency of Lp(a) levels in adults is very high, considerably higher than that of BP, serum lipid levels, and C-reactive protein concentration. Contrary to previous reports of no associations with CHD risk4,15,45 or of effects at only very high Lp(a) levels, the present, much larger-scale data indicate an approximately continuous relationship. In direct comparisons with several established and emerging markers, we showed that the OR for CHD with elevated Lp(a) levels is comparable to those with systolic BP and at least as strong as those with C-reactive protein27 and triglycerides.49 However, whereas ORs with C-reactive protein27 or triglycerides49 in this population attenuated considerably after adjustment for established risk factors (eg, smoking status, lipids, BP, diabetes mellitus, and body mass index), the OR with Lp(a) changed very little after such adjustment. This observation suggests that Lp(a) levels are associated with CHD risk independent of such factors. We showed that ORs for CHD with Lp(a) levels were similar in a range of clinically relevant subgroups, such as in men and women, or at different levels of established risk factors and under different blood handling, storage, and assay conditions.

These findings may have several implications for the development of CHD prevention strategies. First, the demonstration of high consistency of Lp(a) levels within individuals across many years emphasizes the lipoprotein's lack of substantial correlation with lifestyle characteristics or with several established risk factors (as shown in the cross-sectional analyses) and underscores the strong influence of the LPA locus on Lp(a) levels.50 Such high reproducibility suggests the simplifying conclusion that, unlike many other biomarkers, most of the effect of Lp(a) on CHD risk can be assessed using a single measurement. Second, by reliably showing that there are progressively higher ORs for CHD with increasing Lp(a) levels, we have renewed interest in existing and new strategies to modify Lp(a) levels. The demonstration of moderately strong ORs for CHD with elevated Lp(a) levels independent of several established risk factors should encourage studies that can help determine whether Lp(a) levels are causally involved in CHD. Large randomized trials of niacin in CHD prevention are already in progress (eg, HPS2-THRIVE [Heart Protection Study 2 Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events]), although this agent raises high-density lipoprotein cholesterol levels and lowers low-density lipoprotein cholesterol and triglycerides in addition to lowering Lp(a) levels.51 Studies of CHD that use specific LPA genetic variants as proxies for circulating Lp(a) levels should also reduce potential biases, but they may need to be very large.50,52,53

The strengths and potential limitations of the present study merit careful consideration. These new data involve approximately 3 times as many incident CHD cases as the previous largest study32 that quantitatively assessed Lp(a) levels. We identified participants in population registers, had high response and follow-up rates, used robust methods to ascertain CHD outcomes, and minimized potential biases by excluding individuals with prevalent CHD or stroke. Concomitant measurements of several established and emerging markers enabled direct comparisons of ORs with different markers and allowed adjustment for a range of possible confounding factors, although the latter was somewhat limited owing to a lack of data on low- and high-density lipoprotein cholesterol (but previously published studies have reported only weak associations of Lp[a] with these lipid subfractions5456 and little effect on ORs for CHD after adjustment for them35,39). The present Lp(a) assay involved a detection antibody directed toward the Apo(B-100) component of the Lp(a) particle, and, hence, the measurement of Lp(a) levels was not sensitive to Apo(a) isoforms.25,57 The validity of the assay was confirmed by the observation of high decade-to-decade reproducibility in Lp(a) levels. However, because the present measurements did not provide specific information about Apo(a) isoforms (or record oxidized low-density lipoprotein), they could not test suggestions proposed in earlier studies of particularly strong associations with smaller-sized Lp(a) particles58 or in the presence of markers of oxidative damage.59 The present large-scale new data, reinforced by an updated meta-analysis of 31 long-term prospective studies, suggest only modest heterogeneity in OR for CHD with Lp(a) levels despite diversity of assay methods23 and variability in Lp(a) levels across populations. Despite substantial differences noted in Lp(a) levels among studies, none of the factors recorded (eg, features related to blood handling, storage, or assay conditions) in this updated review yielded important differences in ORs (apart from the possibility of more extreme results in studies involving serum rather than plasma, an exploratory finding that requires further investigation). A more detailed exploration of potential sources of heterogeneity requires collaborative pooling of individual participant data from prospective studies.60 Further studies are needed in racial groups, such as in people of African descent, in whom Lp(a) levels are particularly high.61

In conclusion, we observed, under various circumstances, continuous associations between Lp(a) levels and CHD risk apparently independent of the effect of several established cardiovascular risk factors. Levels of Lp(a) are highly stable within individuals across many years and are only weakly correlated with known risk factors. Further assessment of their role in CHD prevention is warranted.

Correspondence: John Danesh, FRCP, DPhil, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, England.

Accepted for Publication: October 28, 2007.

Author Contributions: Drs Bennet and Di Angelantonio contributed equally to this work and are considered joint first authors. Study concept and design: Danesh and Gudnason. Acquisition of data: Eiriksdottir, Sigurdsson, Rumley, Lowe, Danesh, and Gudnason. Analysis and interpretation of data: Bennet, Di Angelantonio, Erqou, Sigurdsson, Woodward, and Danesh. Drafting of the manuscript: Bennet, Di Angelantonio, and Danesh. Critical revision of the manuscript for important intellectual content: Bennet, Di Angelantonio, Erqou, Eiriksdottir, Sigurdsson, Woodward, Rumley, Lowe, Danesh, and Gudnason. Statistical analysis: Bennet, Di Angelantonio, Erqou, and Woodward. Obtained funding: Sigurdsson and Danesh. Administrative, technical, and material support: Sigurdsson and Rumley. Study supervision: Lowe, Danesh, and Gudnason.

Financial Disclosure: None reported.

Funding/Support: This study was supported by a program grant from the British Heart Foundation (Drs Lowe, Danesh, and Gudnason) and by the Raymond and Beverly Sackler Research Award in the Medical Sciences (Dr Danesh). Aspects of the study were supported by an unrestricted educational grant from GlaxoSmithKline (Dr Danesh).

Additional Contributions: The following investigators provided additional information from their studies: Ian Ford, PhD, Barbara Howard, PhD, Paul Ridker, MD, Veikko Salomaa, MD, PhD, and Leon Simons, MD. Adam Butterworth, MSc, Philip Perry, MD, Mark B. Pepys, MD, PhD, FRCP, FRS, FMedSci, and Kausik Ray, MD, MPhil, commented helpfully. Estelle Poorhang and Paul Welsh provided technical assistance.

This article was corrected for typographical errors on 3/24/2008.

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Danesh  JCollins  RPeto  R Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation 2000;102 (10) 1082- 1085
PubMed Link to Article
Cremer  PNagel  DLabrot  B  et al.  Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994;24 (7) 444- 453
PubMed Link to Article
Marcovina  SMKoschinsky  MLAlbers  JJSkarlatos  S Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem 2003;49 (11) 1785- 1796
Link to Article
Marcovina  SMAlbers  JJScanu  AM  et al.  Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem 2000;46 (12) 1956- 1967
PubMed
Tate  JRRifai  NBerg  K  et al.  International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a), phase I: evaluation of the analytical performance of lipoprotein(a) assay systems and commercial calibrators. Clin Chem 1998;44 (8, pt 1) 1629- 1640
PubMed
Jónsdóttir  LSSigfusson  NGudnason  VSigvaldason  HThorgeirsson  G Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? the Reykjavik Study. J Cardiovasc Risk 2002;9 (2) 67- 76
PubMed Link to Article
Danesh  JWheeler  JGHirschfield  GM  et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350 (14) 1387- 1397
PubMed Link to Article
Easton  DFPeto  JBabiker  A Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 1991;10 (7) 1025- 1035
PubMed Link to Article
Rosner  BWillett  WCSpiegelman  D Correction of logistic regression relative risk estimates and confidence intervals for systematic within-person measurement error. Stat Med 1989;8 (9) 1051- 1069
PubMed Link to Article
Danesh  JCollins  RAppleby  PPeto  R Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998;279 (18) 1477- 1482
PubMed Link to Article
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed Link to Article
Sharrett  ARBallantyne  CMCoady  SA  et al.  Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104 (10) 1108- 1113
PubMed Link to Article
Ariyo  AAThach  CTracy  R Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003;349 (22) 2108- 2115
PubMed Link to Article
Gaw  ABrown  EADocherty  GFord  I Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? a nested case control study from the West of Scotland Coronary Prevention Study. Atherosclerosis 2000;148 (1) 95- 100
PubMed Link to Article
Luc  GBard  JMArveiler  D  et al.  Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis 2002;163 (2) 377- 384
PubMed Link to Article
Simons  LASimons  JFriedlander  Y McCallum  J Risk factors for acute myocardial infarction in the elderly (the Dubbo study). Am J Cardiol 2002;89 (1) 69- 72
PubMed Link to Article
Sweetnam  PMBolton  CHDowns  LG  et al.  Apolipoproteins A-I, A-II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly study. Eur J Clin Invest 2000;30 (11) 947- 956
PubMed Link to Article
Suk Danik  JRifai  NBuring  JERidker  PM Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006;296 (11) 1363- 1370
PubMed Link to Article
Shai  IRimm  EBHankinson  SE  et al.  Lipoprotein(a) and coronary heart disease among women: beyond a cholesterol carrier? Eur Heart J 2005;26 (16) 1633- 1639
PubMed Link to Article
Wang  WHu  DLee  ET  et al.  Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease: the Strong Heart Study. Ann Epidemiol 2002;12 (2) 107- 114
PubMed Link to Article
Price  JFLee  AJRumley  ALowe  GDFowkes  FG Lipoprotein(a) and development of intermittent claudication and major cardiovascular events in men and women: the Edinburgh Artery Study. Atherosclerosis 2001;157 (1) 241- 249
PubMed Link to Article
Kronenberg  FKronenberg  MFKiechl  S  et al.  Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 1999;100 (11) 1154- 1160
PubMed Link to Article
Seed  MAyres  KLHumphries  SEMiller  GJ Lipoprotein(a) as a predictor of myocardial infarction in middle-aged men. Am J Med 2001;110 (1) 22- 27
PubMed Link to Article
Cantin  BDespres  JPLamarche  B  et al.  Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study). Am J Cardiol 2002;89 (6) 662- 666
PubMed Link to Article
Evans  RWShpilberg  OShaten  BJAli  SKamboh  MIKuller  LH Prospective association of lipoprotein(a) concentrations and apo(a) size with coronary heart disease among men in the Multiple Risk Factor Intervention Trial. J Clin Epidemiol 2001;54 (1) 51- 57
PubMed Link to Article
Rajecki  MPajunen  PJousilahti  PRasi  VVahtera  ESalomaa  V Hemostatic factors as predictors of stroke and cardiovascular diseases: the FINRISK ’92 Hemostasis Study. Blood Coagul Fibrinolysis 2005;16 (2) 119- 124
PubMed Link to Article
Thøgersen  AMSoderberg  SJansson  JH  et al.  Interactions between fibrinolysis, lipoproteins and leptin related to a first myocardial infarction. Eur J Cardiovasc Prev Rehabil 2004;11 (1) 33- 40
PubMed Link to Article
Seman  LJDeLuca  CJenner  JL  et al.  Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem 1999;45 (7) 1039- 1046
PubMed
Sarwar  NDanesh  JEiriksdottir  G  et al.  Triglycerides and the risk of coronary heart disease: 10 158 incident cases among 262 525 participants in 29 Western prospective studies. Circulation 2007;115 (4) 450- 458
PubMed Link to Article
Boerwinkle  ELeffert  CCLin  JLackner  CChiesa  GHobbs  HH Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992;90 (1) 52- 60
PubMed Link to Article
McKenney  JMJones  PHBays  HE  et al.  Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis 2007;192 (2) 432- 437
PubMed Link to Article
Mooser  VScheer  DMarcovina  SM  et al.  The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet 1997;61 (2) 402- 417
PubMed Link to Article
Boomsma  DIKnijff  PKaptein  A  et al.  The effect of apolipoprotein(a)-, apolipoprotein E-, and apolipoprotein A4- polymorphisms on quantitative lipoprotein(a) concentrations. Twin Res 2000;3 (3) 152- 158
PubMed
Howard  BVLe  NABelcher  JD  et al.  Concentrations of Lp(a) in black and white young adults: relations to risk factors for cardiovascular disease. Ann Epidemiol 1994;4 (5) 341- 350
PubMed Link to Article
Tavridou  AUnwin  NBhopal  RLaker  MF Predictors of lipoprotein(a) levels in a European and South Asian population in the Newcastle Heart Project. Eur J Clin Invest 2003;33 (8) 686- 692
PubMed Link to Article
Braeckman  LDe  BDRosseneu  MDe  BG Determinants of lipoprotein(a) levels in a middle-aged working population. Eur Heart J 1996;17 (12) 1808- 1813
PubMed Link to Article
Marcovina  SMAlbers  JJGabel  BKoschinsky  MLGaur  VP Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem 1995;41 (2) 246- 255
PubMed
Marcovina  SMKoschinsky  ML A critical evaluation of the role of Lp(a) in cardiovascular disease: can Lp(a) be useful in risk assessment? Semin Vasc Med 2002;2 (3) 335- 344
PubMed Link to Article
Tsimikas  SBrilakis  ESMiller  ER  et al.  Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005;353 (1) 46- 57
PubMed Link to Article
Emerging Risk Factors Collaboration, The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. Eur J Epidemiol 2007;22 (12) 839- 869
PubMed Link to Article
Marcovina  SMAlbers  JJWijsman  EZhang  ZChapman  NHKennedy  H Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res 1996;37 (12) 2569- 2585
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Direct comparisons of lipoprotein(a) values, several established cardiovascular risk factors, and emerging markers in relation to within-person variability across 12 years (expressed as the regression dilution ratio [calculated using the Rosner multivariate regression method, adjusted for baseline age, sex, smoking history, diabetes mellitus history, total cholesterol, log triglycerides, systolic blood pressure, and body mass index]) (A) and odds ratios (top third vs bottom third) for coronary heart disease (CHD) (adjusted for established risk factors [age, sex, period of recruitment, smoking status, history of diabetes mellitus, total cholesterol, log triglycerides, systolic blood pressure, and body mass index]) (B). *Regression dilution ratios were calculated using the log-transformed variables. Error bars represent 95% confidence intervals.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Odds ratios for coronary heart disease by fifths (F) of baseline lipoprotein(a) levels adjusted for age, sex, period of recruitment, smoking status, and other established risk factors (total cholesterol, log triglycerides, systolic blood pressure, history of diabetes mellitus, and body mass index). The size of the data markers is proportional to the inverse of the variance of the odds ratios. Fifths were calculated on the basis of the distribution of controls. Geometric mean baseline lipoprotein(a) values in each F were as follows: F1, 3.49 mg/L; F2, 35.29 mg/L; F3, 84.23 mg/L; F4, 171.30 mg/L; and F5, 383.42 mg/L (to convert to micromoles per liter, multiply by 0.0357). Test for linear trend of odds ratios across fifths of lipoprotein(a) levels: P < .001. Error bars represent 95% confidence intervals (CIs) (calculated using floating variances).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Investigation of possible sources of heterogeneity in associations between lipoprotein(a) (Lp[a]) levels and risk of coronary heart disease (CHD) involving individual characteristics in the Reykjavik Study (A) and study-level characteristics in an updated meta-analysis of 31 studies (B). Values are adjusted for age, sex, smoking status, total cholesterol (to convert to millimoles per liter, multiply by 0.0259), log triglycerides (to convert to millimoles per liter, multiply by 0.0113), systolic blood pressure, body mass index, and history of diabetes mellitus. The size of the data markers is proportional to the inverse of the variance of the odds ratios. Thirds of systolic blood pressure, total cholesterol, triglycerides, and tissue plasminogen activator antigen were defined by their respective distributions in cases. Apart from heterogeneity for publication period (P = .004) and sample type (P = .003), there was no evidence of significant interaction between the different subgroups and Lp(a) levels. Error bars represent 95% confidence intervals. To convert C-reactive protein to nanomoles per liter, multiply by 9.524.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Odds ratios for coronary heart disease (CHD) (top third vs bottom third) in each of 31 published prospective studies of lipoprotein(a) in essentially general populations. Heterogeneity: χ230 = 52.6; P = .007: I2 = 43% (95% confidence interval [CI], 12%-63%). ARIC indicates Atherosclerosis Risk in Communities; BUPA, British United Provident Association; GRIPS, Göttingen Risk, Incidence and Prevalence Study; Lip Res Clin Prev Trial, Lipid Research Clinics Coronary Primary Prevention Trial; MONICA, Monitoring Trends and Determinants in Cardiovascular Disease; MRFIT, Multiple Risk Factor Intervention Trial; PRIME, Prospective Epidemiological Study of Myocardial Infarction; PROCAM, Prospective Cardiovascular Münster Study; VIP, Västerbotten Intervention Project; WHS, Women's Health Study; and WOSCOPS, West of Scotland Coronary Prevention Study. Error bars represent 95% CIs.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients With Coronary Heart Disease and Controls in the Reykjavik Study
Table Graphic Jump LocationTable 2. Relative Odds for CHD in Participants Without Known Coronary Disease at Baselinea in a Comparison of Extreme Thirdsb of Baseline Lp(a) Levels
Table Graphic Jump LocationTable 3. Population Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations
Table Graphic Jump LocationTable 4. Laboratory Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations

References

Marcovina  SMKoschinsky  ML Lipoprotein(a) as a risk factor for coronary artery disease. Am J Cardiol 1998;82 (12A) 57U- 66U
PubMed Link to Article
Berglund  LRamakrishnan  R Lipoprotein(a): an elusive cardiovascular risk factor. Arterioscler Thromb Vasc Biol 2004;24 (12) 2219- 2226
PubMed Link to Article
Dahlén  GHWeinehall  LStenlund  H  et al.  Lipoprotein(a) and cholesterol levels act synergistically and apolipoprotein A-I is protective for the incidence of primary acute myocardial infarction in middle-aged males: an incident case-control study from Sweden. J Intern Med 1998;244 (5) 425- 430
PubMed Link to Article
Cantin  BGagnon  FMoorjani  S  et al.  Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? the Quebec Cardiovascular Study. J Am Coll Cardiol 1998;31 (3) 519- 525
PubMed Link to Article
Cremer  PNagel  DMann  H  et al.  Ten-year follow-up results from the Goettingen Risk, Incidence and Prevalence Study (GRIPS), I: risk factors for myocardial infarction in a cohort of 5790 men. Atherosclerosis 1997;129 (2) 221- 230
PubMed Link to Article
Nguyen  TTEllefson  RDHodge  DOBailey  KRKottke  TEAbu-Lebdeh  HS Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women. Circulation 1997;96 (5) 1390- 1397
PubMed Link to Article
Klausen  ICSjol  AHansen  PS  et al.  Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study. Atherosclerosis 1997;132 (1) 77- 84
PubMed Link to Article
Wild  SHFortmann  SPMarcovina  SM A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Arterioscler Thromb Vasc Biol 1997;17 (2) 239- 245
PubMed Link to Article
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PubMed Link to Article
Assmann  GSchulte  Hvon Eckardstein  A Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol 1996;77 (14) 1179- 1184
PubMed Link to Article
Bostom  AGGagnon  DRCupples  LA  et al.  A prospective investigation of elevated lipoprotein(a) detected by electrophoresis and cardiovascular disease in women: the Framingham Heart Study. Circulation 1994;90 (4) 1688- 1695
PubMed Link to Article
Alfthan  GPekkanen  JJauhiainen  M  et al.  Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106 (1) 9- 19
PubMed Link to Article
Wald  NJLaw  MWatt  HC  et al.  Apolipoproteins and ischaemic heart disease: implications for screening. Lancet 1994;343 (8889) 75- 79
PubMed Link to Article
Schaefer  EJLamon-Fava  SJenner  JL  et al.  Lipoprotein(a) levels and risk of coronary heart disease in men: the Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994;271 (13) 999- 1003
PubMed Link to Article
Ridker  PMHennekens  CHStampfer  MJ A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993;270 (18) 2195- 2199
PubMed Link to Article
Sigurdsson  GBaldursdottir  ASigvaldason  HAgnarsson  UThorgeirsson  GSigfusson  N Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men. Am J Cardiol 1992;69 (16) 1251- 1254
PubMed Link to Article
Coleman  MPKey  TJWang  DY  et al.  A prospective study of obesity, lipids, apolipoproteins and ischaemic heart disease in women. Atherosclerosis 1992;92 (2-3) 177- 185
PubMed Link to Article
Jauhiainen  MKoskinen  PEhnholm  C  et al.  Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 1991;89 (1) 59- 67
PubMed Link to Article
Rosengren  AWilhelmsen  LEriksson  ERisberg  BWedel  H Lipoprotein(a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. BMJ 1990;301 (6763) 1248- 1251
PubMed Link to Article
Dahlén  G Lipoprotein (a) as a risk factor for atherosclerotic diseases. Arctic Med Res 1988;47 ((suppl 1)) 458- 461
PubMed
Danesh  JCollins  RPeto  R Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation 2000;102 (10) 1082- 1085
PubMed Link to Article
Cremer  PNagel  DLabrot  B  et al.  Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994;24 (7) 444- 453
PubMed Link to Article
Marcovina  SMKoschinsky  MLAlbers  JJSkarlatos  S Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem 2003;49 (11) 1785- 1796
Link to Article
Marcovina  SMAlbers  JJScanu  AM  et al.  Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem 2000;46 (12) 1956- 1967
PubMed
Tate  JRRifai  NBerg  K  et al.  International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a), phase I: evaluation of the analytical performance of lipoprotein(a) assay systems and commercial calibrators. Clin Chem 1998;44 (8, pt 1) 1629- 1640
PubMed
Jónsdóttir  LSSigfusson  NGudnason  VSigvaldason  HThorgeirsson  G Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? the Reykjavik Study. J Cardiovasc Risk 2002;9 (2) 67- 76
PubMed Link to Article
Danesh  JWheeler  JGHirschfield  GM  et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350 (14) 1387- 1397
PubMed Link to Article
Easton  DFPeto  JBabiker  A Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 1991;10 (7) 1025- 1035
PubMed Link to Article
Rosner  BWillett  WCSpiegelman  D Correction of logistic regression relative risk estimates and confidence intervals for systematic within-person measurement error. Stat Med 1989;8 (9) 1051- 1069
PubMed Link to Article
Danesh  JCollins  RAppleby  PPeto  R Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998;279 (18) 1477- 1482
PubMed Link to Article
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed Link to Article
Sharrett  ARBallantyne  CMCoady  SA  et al.  Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104 (10) 1108- 1113
PubMed Link to Article
Ariyo  AAThach  CTracy  R Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003;349 (22) 2108- 2115
PubMed Link to Article
Gaw  ABrown  EADocherty  GFord  I Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? a nested case control study from the West of Scotland Coronary Prevention Study. Atherosclerosis 2000;148 (1) 95- 100
PubMed Link to Article
Luc  GBard  JMArveiler  D  et al.  Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis 2002;163 (2) 377- 384
PubMed Link to Article
Simons  LASimons  JFriedlander  Y McCallum  J Risk factors for acute myocardial infarction in the elderly (the Dubbo study). Am J Cardiol 2002;89 (1) 69- 72
PubMed Link to Article
Sweetnam  PMBolton  CHDowns  LG  et al.  Apolipoproteins A-I, A-II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly study. Eur J Clin Invest 2000;30 (11) 947- 956
PubMed Link to Article
Suk Danik  JRifai  NBuring  JERidker  PM Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006;296 (11) 1363- 1370
PubMed Link to Article
Shai  IRimm  EBHankinson  SE  et al.  Lipoprotein(a) and coronary heart disease among women: beyond a cholesterol carrier? Eur Heart J 2005;26 (16) 1633- 1639
PubMed Link to Article
Wang  WHu  DLee  ET  et al.  Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease: the Strong Heart Study. Ann Epidemiol 2002;12 (2) 107- 114
PubMed Link to Article
Price  JFLee  AJRumley  ALowe  GDFowkes  FG Lipoprotein(a) and development of intermittent claudication and major cardiovascular events in men and women: the Edinburgh Artery Study. Atherosclerosis 2001;157 (1) 241- 249
PubMed Link to Article
Kronenberg  FKronenberg  MFKiechl  S  et al.  Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 1999;100 (11) 1154- 1160
PubMed Link to Article
Seed  MAyres  KLHumphries  SEMiller  GJ Lipoprotein(a) as a predictor of myocardial infarction in middle-aged men. Am J Med 2001;110 (1) 22- 27
PubMed Link to Article
Cantin  BDespres  JPLamarche  B  et al.  Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study). Am J Cardiol 2002;89 (6) 662- 666
PubMed Link to Article
Evans  RWShpilberg  OShaten  BJAli  SKamboh  MIKuller  LH Prospective association of lipoprotein(a) concentrations and apo(a) size with coronary heart disease among men in the Multiple Risk Factor Intervention Trial. J Clin Epidemiol 2001;54 (1) 51- 57
PubMed Link to Article
Rajecki  MPajunen  PJousilahti  PRasi  VVahtera  ESalomaa  V Hemostatic factors as predictors of stroke and cardiovascular diseases: the FINRISK ’92 Hemostasis Study. Blood Coagul Fibrinolysis 2005;16 (2) 119- 124
PubMed Link to Article
Thøgersen  AMSoderberg  SJansson  JH  et al.  Interactions between fibrinolysis, lipoproteins and leptin related to a first myocardial infarction. Eur J Cardiovasc Prev Rehabil 2004;11 (1) 33- 40
PubMed Link to Article
Seman  LJDeLuca  CJenner  JL  et al.  Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem 1999;45 (7) 1039- 1046
PubMed
Sarwar  NDanesh  JEiriksdottir  G  et al.  Triglycerides and the risk of coronary heart disease: 10 158 incident cases among 262 525 participants in 29 Western prospective studies. Circulation 2007;115 (4) 450- 458
PubMed Link to Article
Boerwinkle  ELeffert  CCLin  JLackner  CChiesa  GHobbs  HH Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992;90 (1) 52- 60
PubMed Link to Article
McKenney  JMJones  PHBays  HE  et al.  Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis 2007;192 (2) 432- 437
PubMed Link to Article
Mooser  VScheer  DMarcovina  SM  et al.  The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet 1997;61 (2) 402- 417
PubMed Link to Article
Boomsma  DIKnijff  PKaptein  A  et al.  The effect of apolipoprotein(a)-, apolipoprotein E-, and apolipoprotein A4- polymorphisms on quantitative lipoprotein(a) concentrations. Twin Res 2000;3 (3) 152- 158
PubMed
Howard  BVLe  NABelcher  JD  et al.  Concentrations of Lp(a) in black and white young adults: relations to risk factors for cardiovascular disease. Ann Epidemiol 1994;4 (5) 341- 350
PubMed Link to Article
Tavridou  AUnwin  NBhopal  RLaker  MF Predictors of lipoprotein(a) levels in a European and South Asian population in the Newcastle Heart Project. Eur J Clin Invest 2003;33 (8) 686- 692
PubMed Link to Article
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