 |
|
Lipoprotein(a) Levels and Risk of Future Coronary Heart DiseaseLarge-Scale Prospective Data
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
Arch Intern Med. 2008;168(6):598-608.
ABSTRACT
| |
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.
INTRODUCTION
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 studies3-20 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).
METHODS
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  2 tests and the I 2 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.
RESULTS
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.
|
|
|
|
Table 1. Baseline Characteristics of Patients With Coronary Heart Disease and Controls in the Reykjavik Study
|
|
|
|
|
|
|
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.
|
|
|
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).32-47
|
|
|
|
Table 2. Relative Odds for CHD in Participants Without Known Coronary Disease at Baselinea in a Comparison of Extreme Thirdsb of Baseline Lp(a) Levels
|
|
|
|
|
|
|
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).
|
|
|
|
|
|
|
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.
|
|
|
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 2000.32-41,43-46 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, 32-35,39-42,44, 46-48 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 (2 30 = 52.6; P = .007; I 2 = 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).
|
|
|
|
Table 3. Population Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations
|
|
|
|
|
|
|
Table 4. Laboratory Characteristics of 31 Prospective Studies of Lp(a) and CHD in Essentially General Populations
|
|
|
|
|
|
|
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: 2 30 = 52.6; P = .007: I 2 = 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.
|
|
|
COMMENT
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 subfractions54-56 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.
AUTHOR INFORMATION
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.
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).
REFERENCES
| |
1. Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for coronary artery disease. Am J Cardiol. 1998;82(12A):57U-66U.
FULL TEXT
|
ISI
| PUBMED
2. Berglund L, Ramakrishnan R. Lipoprotein(a): an elusive cardiovascular risk factor. Arterioscler Thromb Vasc Biol. 2004;24(12):2219-2226.
FREE FULL TEXT
3. Dahlén GH, Weinehall L, Stenlund 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.
FULL TEXT
|
ISI
| PUBMED
4. Cantin B, Gagnon F, Moorjani 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.
FREE FULL TEXT
5. Cremer P, Nagel D, Mann 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.
FULL TEXT
|
ISI
| PUBMED
6. Nguyen TT, Ellefson RD, Hodge DO, Bailey KR, Kottke TE, Abu-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.
FREE FULL TEXT
7. Klausen IC, Sjol A, Hansen PS; et al. Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study. Atherosclerosis. 1997;132(1):77-84.
FULL TEXT
|
ISI
| PUBMED
8. Wild SH, Fortmann SP, Marcovina 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.
FREE FULL TEXT
9. Bostom AG, Cupples LA, Jenner JL; et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger: a prospective study. JAMA. 1996;276(7):544-548.
FREE FULL TEXT
10. Assmann G, Schulte H, von 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.
FULL TEXT
|
ISI
| PUBMED
11. Bostom AG, Gagnon DR, Cupples 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.
FREE FULL TEXT
12. Alfthan G, Pekkanen J, Jauhiainen 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.
FULL TEXT
|
ISI
| PUBMED
13. Wald NJ, Law M, Watt HC; et al. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet. 1994;343(8889):75-79.
FULL TEXT
|
ISI
| PUBMED
14. Schaefer EJ, Lamon-Fava S, Jenner 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.
FREE FULL TEXT
15. Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA. 1993;270(18):2195-2199.
FREE FULL TEXT
16. Sigurdsson G, Baldursdottir A, Sigvaldason H, Agnarsson U, Thorgeirsson G, Sigfusson N. Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men. Am J Cardiol. 1992;69(16):1251-1254.
FULL TEXT
|
ISI
| PUBMED
17. Coleman MP, Key TJ, Wang DY; et al. A prospective study of obesity, lipids, apolipoproteins and ischaemic heart disease in women. Atherosclerosis. 1992;92(2-3):177-185.
FULL TEXT
|
ISI
| PUBMED
18. Jauhiainen M, Koskinen P, Ehnholm 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.
FULL TEXT
|
ISI
| PUBMED
19. Rosengren A, Wilhelmsen L, Eriksson E, Risberg B, Wedel 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.
FREE FULL TEXT
20. Dahlén G. Lipoprotein (a) as a risk factor for atherosclerotic diseases. Arctic Med Res. 1988;47(suppl 1):458-461.
21. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation. 2000;102(10):1082-1085.
FREE FULL TEXT
22. Cremer P, Nagel D, Labrot 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.
ISI
| PUBMED
23. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos 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.
FREE FULL TEXT
24. Marcovina SM, Albers JJ, Scanu 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.
FREE FULL TEXT
25. Tate JR, Rifai N, Berg 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.
FREE FULL TEXT
26. Jónsdóttir LS, Sigfusson N, Gudnason V, Sigvaldason H, Thorgeirsson 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.
FULL TEXT
|
ISI
| PUBMED
27. Danesh J, Wheeler JG, Hirschfield 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.
FREE FULL TEXT
28. Easton DF, Peto J, Babiker 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.
ISI
| PUBMED
29. Rosner B, Willett WC, Spiegelman D. Correction of logistic regression relative risk estimates and confidence intervals for systematic within-person measurement error. Stat Med. 1989;8(9):1051-1069.
ISI
| PUBMED
30. Danesh J, Collins R, Appleby P, Peto 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.
FREE FULL TEXT
31. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
FREE FULL TEXT
32. Sharrett AR, Ballantyne CM, Coady 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.
FREE FULL TEXT
33. Ariyo AA, Thach C, Tracy R. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med. 2003;349(22):2108-2115.
FREE FULL TEXT
34. Gaw A, Brown EA, Docherty G, Ford 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.
FULL TEXT
|
ISI
| PUBMED
35. Luc G, Bard JM, Arveiler D; et al. Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis. 2002;163(2):377-384.
FULL TEXT
|
ISI
| PUBMED
36. Simons LA, Simons J, Friedlander Y, McCallum J. Risk factors for acute myocardial infarction in the elderly (the Dubbo study). Am J Cardiol. 2002;89(1):69-72.
FULL TEXT
|
ISI
| PUBMED
37. Sweetnam PM, Bolton CH, Downs 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.
FULL TEXT
|
ISI
| PUBMED
38. Suk Danik J, Rifai N, Buring JE, Ridker 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.
FREE FULL TEXT
39. Shai I, Rimm EB, Hankinson SE; et al. Lipoprotein(a) and coronary heart disease among women: beyond a cholesterol carrier? Eur Heart J. 2005;26(16):1633-1639.
FREE FULL TEXT
40. Wang W, Hu D, Lee 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.
FULL TEXT
|
ISI
| PUBMED
41. Price JF, Lee AJ, Rumley A, Lowe GD, Fowkes 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.
FULL TEXT
|
ISI
| PUBMED
42. Kronenberg F, Kronenberg MF, Kiechl 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.
FREE FULL TEXT
43. Seed M, Ayres KL, Humphries SE, Miller GJ. Lipoprotein(a) as a predictor of myocardial infarction in middle-aged men. Am J Med. 2001;110(1):22-27.
FULL TEXT
|
ISI
| PUBMED
44. Cantin B, Despres JP, Lamarche 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.
FULL TEXT
|
ISI
| PUBMED
45. Evans RW, Shpilberg O, Shaten BJ, Ali S, Kamboh MI, Kuller 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.
FULL TEXT
|
ISI
| PUBMED
46. Rajecki M, Pajunen P, Jousilahti P, Rasi V, Vahtera E, Salomaa V. Hemostatic factors as predictors of stroke and cardiovascular diseases: the FINRISK ’92 Hemostasis Study. Blood Coagul Fibrinolysis. 2005;16(2):119-124.
ISI
| PUBMED
47. Thøgersen AM, Soderberg S, Jansson 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.
FULL TEXT
|
ISI
| PUBMED
48. Seman LJ, DeLuca C, Jenner JL; et al. Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem. 1999;45(7):1039-1046.
FREE FULL TEXT
49. Sarwar N, Danesh J, Eiriksdottir 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.
FREE FULL TEXT
50. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs 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.
ISI
| PUBMED
51. McKenney JM, Jones PH, Bays 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.
FULL TEXT
|
ISI
| PUBMED
52. Mooser V, Scheer D, Marcovina 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.
ISI
| PUBMED
53. Boomsma DI, Knijff P, Kaptein 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.
FULL TEXT
| PUBMED
54. Howard BV, Le NA, Belcher 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
55. Tavridou A, Unwin N, Bhopal R, Laker 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.
FULL TEXT
|
ISI
| PUBMED
56. Braeckman L, De BD, Rosseneu M, De BG. Determinants of lipoprotein(a) levels in a middle-aged working population. Eur Heart J. 1996;17(12):1808-1813.
FREE FULL TEXT
57. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995;41(2):246-255.
FREE FULL TEXT
58. Marcovina SM, Koschinsky 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.
FULL TEXT
| PUBMED
59. Tsimikas S, Brilakis ES, Miller ER; et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353(1):46-57.
FREE FULL TEXT
60. 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.
FULL TEXT
|
ISI
| PUBMED
61. Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res. 1996;37(12):2569-2585.
ABSTRACT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Mendelian Randomization: Nature's Randomized Trial in the Post-Genome Era
Thanassoulis and O'Donnell
JAMA 2009;301:2386-2388.
FULL TEXT
Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions
Choy and Sattar
Ann Rheum Dis 2009;68:460-469.
ABSTRACT
| FULL TEXT
|
