Elsevier

Atherosclerosis

Volume 163, Issue 2, August 2002, Pages 377-384
Atherosclerosis

Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study

https://doi.org/10.1016/S0021-9150(02)00026-6Get rights and content

Abstract

The association of an elevated level of lipoprotein (a) (Lp(a)) with the development of coronary heart disease (CHD) remains controversial. Lp(a) was investigated as a CHD risk factor in the PRIME Study, a prospective cohort study which included 9133 French and Northern Irish men aged 50–59 at entry, without a history of CHD and not on hypolipidaemic drugs. During a follow-up of 5 years, 288 subjects experienced at least one CHD event (myocardial infarction (MI), coronary death, angina pectoris). Lp(a) was measured by immunoassay in all subjects on fresh plasma obtained at entry. Traditional cardiovascular risk factors such as low-density lipoproteins (LDL)-cholesterol, HDL-cholesterol, triglycerides, the presence of diabetes, hypertension or smoking were determined. Logistic regression analysis was used to evaluate Lp(a) level as a CHD risk factor after controlling for the other risk factors. In addition, its possible interaction with LDL- and HDL-cholesterol levels was investigated. Lp(a) appeared a significant risk factor (P<0.0006) in the whole cohort without between-population interaction, even if the association was not statistically significant in the Belfast sample. The relative risk (RR) of CHD events in subjects with Lp(a) levels in the highest quartile was 1.5 times that of subjects in the lowest quartile (RR: 1.56; 95% confidence intervals (CIs): 1.10–2.21). A high Lp(a) level was a risk for MI, coronary death and angina pectoris. A significant interaction term between Lp(a) and LDL-cholesterol levels, however, was found. The relative CHD risk associated with a Lp(a) level ⩾33 mg/dl in comparison with Lp(a) <33 mg/dl increasing gradually from 0.82 (95% CI: 0.28–2.44) in men with LDL-cholesterol in the lowest quartile (<121 mg/dl) to 1.58 (95% CI: 1.06–2.40) in the highest quartile (>163 mg/dl). In conclusion, Lp(a) increased the risk for MI and angina pectoris, especially in men with a high LDL-cholesterol level. This study which analyzed Lp(a) level using a measurement independent of apolipoprotein (a) size on fresh plasma, has confirmed utility of Lp(a) as a predictor of CHD.

Introduction

Lipoprotein (a) (Lp(a)) is a cholesterol-rich lipoprotein with structural similarities to low-density lipoproteins (LDL) [1], but contains apolipoprotein (apo(a)), a glycoprotein with sequence homology to plasminogen [2] and bound by a disulfide bond to apoB100. It is this structure that has raised the hypothesis that Lp(a) may play an important role in promoting coronary atherosclerosis and thrombosis, and it has generated considerable interest.

The majority of retrospective case-control studies have found an association between high Lp(a) values and coronary heart disease (CHD) [3]. Prospective cohort studies are however needed to estimate risk on a firm methodological basis [4]. A recent meta-analysis including 18 prospective cohort studies showed that the relative risk (RR) comparing top and bottom thirds of baseline measurements was 1.7 (P<0.0001), without significant heterogeneity [5]. The interpretation of these data is however complicated by the different methodologies used in measuring plasma Lp(a) and the lack of standardization. Indeed, apo(a) is considerably heterogeneous in size due to a genetically variable number of repeats of basic structure called kringles. Thus, a number of immunological methods of Lp(a) measurements underestimate or overestimate the Lp(a) levels because of the choice of calibrator which can have an apo(a) size different from the tested plasma, and because of a variation in the reactivity of the antibodies directed to the antigenic sites which depends on the apo(a) size [6]. Furthermore, most of prospective studies investigating Lp(a) as a risk factor for CHD have measured Lp(a) in long-term frozen samples. However, a markedly higher decrease of Lp(a) over time was observed in plasma samples with low molecular weight compared with high molecular weight apo(a) isoforms [7]. So, these modifications could have led to bias in a number of prospective or case-control studies.

The PRIME Study is a prospective cohort study set up to investigate the association of different risk factors and the development of CHD in France and Northern Ireland [8]. Furthermore, previous cohort studies have generally analyzed the predictive value of parameters for myocardial infarction (MI) and coronary death—the so-called ‘hard CHD end-points’—but none has made an evaluation of hard CHD cases in comparison with angina pectoris. Finally, it has been suggested by previous studies that high levels of Lp(a) may increase the deleterious effect of elevated LDL-cholesterol and counteract the beneficial effects associated with elevated HDL-cholesterol levels on both the incidence of CHD [9], [10], [11] and the progression of carotid atherosclerosis [12].

In this paper, we have therefore studied different issues: (1) Lp(a) as a risk factor for CHD; (2) its predictive value for hard CHD events or angina; and (3) the possible interaction of Lp(a) with LDL-cholesterol, HDL-cholesterol and apoAI.

Section snippets

Materials and methods

The design of the PRIME Study cohort is described elsewhere [8]. The PRIME Study is of prospective cohort design and population-based. The 1991–1994 intake to the PRIME Study examined 10 600 males aged 50–59 years living in the areas of Lille, Strasbourg and Toulouse in France and Belfast, Northern Ireland. The entry examination included standardized questionnaires relating particularly to medical history, drug intake, presence of CHD and various habits including tobacco consumption. Smoking

Subject characteristics

The general characteristics of cases and controls are shown in Table 1. During follow-up, 175 French and 113 Northern Irish subjects, corresponding to 2.6 and 4.9% of their respective cohorts, suffered coronary events. The percentage of smokers was higher in those with events than in those without. Diabetes mellitus was approximately 2–3-fold commoner in those who developed events than in controls in both countries. Systolic and diastolic blood pressure levels were significantly higher in cases

Discussion

We have analyzed the association between Lp(a) level and CHD incidence amongst French and Northern Irish middle-aged males enrolled in a large, prospective cohort study. Although Lp(a) median levels were only slightly different in Northern Irish cases and controls, the magnitude of the relationship of Lp(a) level to CHD RR did not differ significantly between them. This absence of interaction however may be due to a lack of power and our results obviously cannot exclude the possibility that

Acknowledgments

The authors thank Dr Rémy Couderc for fruitful discussion. We thank the following organizations which allowed the recruitment of the PRIME subjects: the Department of Health of Northern Ireland, the Northern Ireland Chest Heart and Stroke Association, the Health screening centers organized for by the Social Security of Lille (Institut Pasteur of Lille), Strasbourg, Toulouse and Tourcoing; Occupational Medicine Services of Haute-Garonne, of the Urban Community of Strasbourg; the Association

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    The PRIME Study Group. The PRIME Study is organized under an agreement between INSERM and the Merck, Sharpe and Dohme-Chibret Laboratory, with the following participating Laboratories: • The Strasbourg MONICA Project, Department of Epidemiology and Public Health, Faculty of Medicine, Strasbourg, France (D. Arveiler, B. Haas); • The Toulouse MONICA Project, INSERM U558, Department of Epidemiology, Paul Sabatier-Toulouse Purpan University, Toulouse, France (J. Ferrières, J.B.Ruidavets); • The Lille MONICA Project, INSERM U508, Pasteur Institute, Lille, France (P. Amouyel, M. Montaye); • The Department of Epidemiology and Public Health, The Queen's University of Belfast, Belfast, Northern Ireland (A. Evans, J. Yarnell); • The Department of Atherosclerosis, SERLIA – INSERM U325, Lille, France (G. Luc, J.M. Bard, L. Elkhalil, J-C. Fruchart); • The Laboratory of Haematology, La Timone Hospital, Marseilles, France (I. Juhan-Vague); • The Laboratory of Endocrinology, INSERM U326, Toulouse, France (B. Perret); • The Vitamin Research Unit, The University of Bern, Bern, Switzerland (F. Gey); • The Trace Element Laboratory, Department of Medicine, The Queen's University, Belfast, Northern Ireland (D. McMaster); • The DNA Bank, INSERM U525/SC7, Paris, France (F. Cambien); • The Coordinating Center, INSERM U258, Paris-Villejuif, France (P. Ducimetière, P.Y. Scarabin, A. Bingham).

    1

    Present address: Faculty of Pharmacy, Nantes, France.

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