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(Circulation. 1996;94:273-278.)
© 1996 American Heart Association, Inc.

Articles

Apolipoprotein A-I and B Levels and the Risk of Ischemic Heart Disease During a Five-Year Follow-up of Men in the Quebec Cardiovascular Study

Benoit Lamarche, MSc; Sital Moorjani, PhD; Paul J. Lupien, MD, PhD; Bernard Cantin, MD; Paul-Marie Bernard, MSc; Gilles R. Dagenais, MD; Jean-Pierre Despres, PhD

the Lipid Research Center, Laval University Hospital Research Center, Ste-Foy (B.L., S.M., P.J.L., B.C., J.-P.D.); the Department of Social and Preventive Medicine, Laval University, Quebec (P.-M.B.); and the Department of Medicine, University of Montreal (G.R.D.), Quebec, Canada.

Correspondence to Dr Jean-Pierre Despres, PhD, Professor and Director, Lipid Research Center, CHUL Research Center, 2705 Laurier Blvd, Ste-Foy, Quebec, Canada G1V 4G2. E-mail jpierre.despres@crchul.ulaval.ca.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Results obtained largely from case-control studies have suggested that an elevated plasma concentration of apolipoprotein (apo) B may be considered an important risk factor for ischemic heart disease (IHD). Prospective data on the relevance of measuring apo A-I and apo B levels in the assessment of IHD risk, however, remain sparse as well as controversial.

Methods and Results Plasma lipid, apo B, and apo A-I levels as well as other risk factors were evaluated at baseline in 1985 in a sample of 2155 men (45 to 76 years old) who were followed for a period of 5 years for clinical signs of IHD. Proportional-hazards analyses indicated that plasma apo B concentrations measured at entry were strongly associated with onset of IHD (relative rate, 1.4; 95% confidence interval [CI], 1.2 to 1.7), independent of covariables such as age, smoking, diabetes mellitus, and systolic blood pressure. Controlling for triglycerides, HDL cholesterol, and total/HDL cholesterol ratio did not eliminate the relationship between plasma apo B levels and IHD. The association between apo A-I and IHD was of lower magnitude (relative rate, 0.85; 95% CI, 0.7 to 1.0), and adjustment for selected plasma lipid and lipoprotein levels eliminated this association. Stepwise logistic regression analysis revealed that, among metabolic variables, apo B was the strongest correlate of IHD.

Conclusions These prospective results emphasize the importance of apo B as a risk factor for IHD. Apo B may be regarded as a relevant tool in the assessment of IHD risk in men, because it may provide information that would not be obtained from the conventional lipid-lipoprotein profile.

Key Words: apolipoproteins • ischemia • heart diseases • lipoproteins

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Plasma LDL and HDL cholesterol are important risk factors for ischemic heart disease (IHD).^{1 2 3 4 5} In addition, indices such as total/HDL and LDL/HDL cholesterol ratios are considered to be powerful predictors of IHD.^{4 6 7} It has been suggested that apolipoprotein (apo) B, the protein moiety of LDL, and apo A-I, the principal protein component of HDL, may also be relevant predictors of IHD.^{8 9 10 11 12} There is evidence from case-control studies that apos B and A-I may be superior to LDL and HDL cholesterol in discriminating IHD case subjects from control subjects.^{13 14 15 16} The supporting evidence from prospective studies, however, is not only sparse but also rather inconsistent.^{7 17 18 19} Whether apo B and apo A-I measurements provide any additional information other than that obtained from the usual lipoprotein-lipid profile in the risk assessment of IHD remains controversial^{20 21 22} and requires further prospective eval-uation. In this study, we investigated the relationships between apo A-I and apo B levels and IHD in 2155 men from the Quebec Cardiovascular Study using 5-year survival data obtained between 1985 and 1990. The relative contributions of various cholesterol indices and of apolipoprotein measurements along with other risk factors to the development of IHD are also reported.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Cohort and Follow-up
The cohort has been described in detail previously.^{23 24} Briefly, a random sample of 4637 men (35 to 64 years old), 99% of whom were of French Canadian descent, was recruited in 1973 from the Quebec city metropolitan area to assess the prevalence of cardiovascular disease risk factors, which also included the measurement of nonfasting cholesterol levels. Men with clinical evidence of IHD (n=266) were excluded from further follow-up. In 1985 through 1986, a new evaluation of risk factors, including fasting lipoprotein-lipid levels and apo B and A-I concentrations, was performed in 53% of the men (n=2443) who had participated in the 1973 initial screening. Among the remaining 1928 men of the 1973 evaluation, 19% (n=371) had died, 8% could not be located, 15% came to the clinic nonfasting, and the remaining 58% either refused to participate or were evaluated in a nonfasting state at home by nurses working for the project. Analyses of data collected in 1973 revealed that the age distribution of the 2443 participants was representative of the original cohort and that there were no differences between the participants and the 1928 nonparticipants for IHD mortality.²⁵ In 1990 through 1991, participants were contacted by mail and invited to answer a short standardized questionnaire based on smoking habits, medication, and history of cardiovascular disease and diabetes mellitus. Telephone calls were made to participants who did not answer a second letter or, if unsuccessful, to a close family member. Mortality data were obtained in 99% of the 1973 cohort. After exclusion of men with IHD in 1985 (n=250) and those for whom no follow-up data were available (n=38), we performed the analyses on a cohort of 2155 men free of clinical signs of IHD at entry in 1985.

Evaluation of Risk Factors
The data on demographic and lifestyle variables as well as medical history and medication were collected at baseline (in 1985) through a standardized questionnaire administered by trained nurses and further reviewed by physicians. Questionnaires provided the following information: family and personal histories of cardiovascular disease and diabetes, smoking habits, alcohol consumption, and medication use. Use of hypolipidemic drugs, mainly clofibrate and cholestyramine in 1985, was limited to 1% of men both with and without IHD. Regular use of ß-blockers (10.5% versus 5.6%) and diuretics (7% versus 2.8%) at baseline was higher in men who eventually developed IHD during follow-up (P<.001). Alcohol intake was computed from the type of beverage (beer, wine, and spirits) consumed in ounces per week and then standardized as absolute amount, 1 oz of absolute alcohol being equivalent to 22.5 g alcohol.²⁶ Body weight and height were recorded. Resting blood pressure measurements were performed after a 5-minute rest in a sitting position before blood sampling.

Definition of IHD Events
Criteria used for the diagnosis of IHD have been described extensively.^{23 24} The diagnosis of a first IHD event included typical effort angina, coronary insufficiency, nonfatal myocardial infarction, and coronary death.²⁷ The diagnosis of effort angina was based on typical symptoms of retrosternal squeezing or pressure-type discomfort occurring on exertion and relieved by rest and/or nitroglycerin. The diagnoses of coronary insufficiency and myocardial infarction were confirmed through medical records. Coronary insufficiency was considered if typical retrosternal chest pain of at least 15 minutes' duration was associated with transient suggestive ischemic changes on the ECG (Minnesota codes 5-1 or 5-2) but without significant elevation in levels of creatine phosphokinase. The diagnosis of myocardial infarction was based on an evolutive ECG suggestive of myocardial necrosis (Minnesota code 1-1) or the presence of at least two of the following criteria: ECG changes corresponding to myocardial ischemia (Minnesota codes 1-2-1 to 1-2-5 and 1-2-7) or changes in repolarization (codes 9-2 and 5-1 or 5-2); abnormal creatine phosphokinase enzyme at least twice the upper limit of normal; and typical retrosternal chest pain of at least 20 minutes' duration not relieved by rest and/or nitroglycerin. All ECGs were read by the same cardiologist, who was unaware of the participants' risk profile. Among the 103 men who died between 1985 and 1990, 15 died of IHD, most of them documented in hospital records and all of them confirmed through the provincial death registrate. Criteria for the diagnoses of coronary deaths included confirmation from death certificate or an autopsy report confirming the presence of coronary disease, without evidence for noncardiac or atherosclerotic disease that could explain death. Informed consent from the participants and hospital administration was obtained to review hospital files. Autopsies were performed in about one third of deaths.

Laboratory Analyses
Twelve-hour fasting blood samples were obtained from the antecubital vein while participants were in a sitting position. A tourniquet was used but was released before withdrawal of blood into vacuum tubes containing EDTA. Plasma was separated from blood cells by centrifugation and immediately used for lipid and apolipoprotein measurements. Plasma cholesterol and triglyceride levels were determined on an Auto Analyzer II (Technicon Instruments Corp) as previously described.²⁸ HDL cholesterol was measured in the supernatant fraction after precipitation of apo B–containing lipoproteins with heparin–manganese chloride.²⁹ LDL cholesterol levels were estimated by the equation of Friedewald et al³⁰ for men with triglycerides <4.5 mmol/L. Plasma apo B and A-I levels were measured according to the rocket immunoelectrophoresis method of Laurell³¹ as previously described.²⁸ Serum standards for apolipoprotein determinations were prepared in our laboratory and calibrated against sera from the Centers for Disease Control and Prevention, Atlanta, Ga. Standards were lyophilized and stored at -85°C until use. For both apo A-I and apo B, peak heights between 15 and 35 mm yielded linear and reliable results. The cumulative coefficients of variation were 2.1% for cholesterol, 3.3% for HDL cholesterol, 3.0% for triglyceride, 3.5% for apo B, and 3.4% for apo A-I.

Statistical Analyses
Duration of follow-up was calculated in person-years by use of the follow-up of each participant from the 1985 evaluation until the 1990 or 1991 last contact, death, or onset of IHD. Proportional-hazards models were developed to estimate rate of IHD events according to plasma lipid, lipoprotein, and apolipoprotein levels by use of the PHREG procedure from SAS. Age, systolic blood pressure, diabetes mellitus, smoking, and medication use were included in all models as potential confounders. Preliminary results showed that the relationship between IHD and risk factors was linear across their distribution. For that reason, all variables were treated as continuous in all analyses, with the exception of diabetes mellitus, medication use, and smoking. Diabetes and medication were dichotomized (presence or absence), whereas smoking status at entry was treated as follows: 1, men who never smoked; 2, men who stopped smoking 1 year before the baseline visit; 3, pipe and cigar smokers; 4, men who smoked 1 to 20 cigarettes per day; and 5, those who smoked 20 cigarettes per day. Because weekly alcohol intake was not a risk factor for IHD in this study and because it did not affect the estimates of the other risk factors, alcohol consumption was not considered further in the present analyses. Estimates of hazards ratio (relative rate, RR) of IHD were calculated by use of the coefficients (ß) obtained from the proportional-hazards models. To compare the risk associated with variables having different scales or ranges of values, RRs of the continuous variables were computed as the increase or decrease in risk of IHD associated with an elevation of 1 SD in the level of the risk factors. Missing LDL cholesterol values in men with plasma triglyceride levels >4.5 mmol/L were treated in the analyses by use of an additional category representing the missing data. Multivariate associations between risk factors and IHD were also investigated with stepwise proportional-hazards models. Probability values were set at.05 for both acceptance and rejection of variables in the stepwise procedures. The Kaplan-Meier survival probability (estimated probability of not having IHD during follow-up) was computed for tertiles of apo A-I and B levels. The log-rank test was used to compare parallelism of survival curves among the tertiles of apolipoproteins. Mean baseline characteristics of men who developed IHD and those who remained free of IHD during the 5-year follow-up were compared by Student's t tests. Differences between frequency data were tested by ² analysis. Collinearity diagnosis among variables was obtained by multiple linear regression analysis.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Mean follow-up of the 2155 men evaluated in 1985 through 1986 was 5.0 years and generated 10 775 person-years. Age ranged from 45 to 76 years, with a mean of 56.5 years. Table 1 presents the lipid and lipoprotein profiles of the cohort at baseline. The lipid and lipoprotein values of the random sample of men essentially matched those of the Lipid Research Clinic Study³² and of the Framingham Study³³ for men of similar age. Among the 2155 men free of IHD at entry, 116 developed IHD during follow-up, for an IHD incidence rate of 108 per 10 000 person-years. First IHD events included 50 first cases of myocardial infarction and 51 first cases of effort angina, whereas 15 men died of IHD-related causes. As expected, men who developed IHD during follow-up were older (59 versus 56 years) and had a higher systolic blood pressure (137 versus 130 mm Hg) and a higher prevalence of diabetes mellitus (15.5% versus 4.4%) at baseline compared with men who remained free of IHD (P<.001). The number of smokers at entry tended to be higher in men who developed IHD (44.7% versus 37.3%, P=.11), and this difference could be attributed primarily to the higher prevalence of heavy smokers (20 or more cigarettes per day) in men with IHD compared with men without IHD (32.5% versus 23.0%, respectively, P<.02).

View this table: [in this window] [in a new window]   Table 1. Plasma Lipid, Lipoprotein, and Apolipoprotein Levels Measured at Baseline in the Study Cohort of 2155 Men From the Quebec Cardiovascular Study

Proportional hazards of IHD according to selected plasma lipid, lipoprotein, and apolipoprotein levels are presented in Table 2. Increases in IHD RR associated with an increase of 1 SD in plasma concentration of cholesterol, apo B (RR=1.46 and 1.44, respectively), and LDL cholesterol (not shown) were essentially similar and highly significant after adjustment for confounders (95% CI, 1.2 to 1.7). Elevated apo A-I levels were associated with a decreased RR of IHD (RR=0.85), but this reduction did not reach statistical significance (95% CI, 0.70 to 1.03). The reduction in incidence rate of IHD associated with increased HDL cholesterol levels was of greater magnitude (RR=0.81) than for apo A-I and reached the.05 significance level (95% CI, 0.66 to 0.98).

View this table: [in this window] [in a new window]   Table 2. Cox Proportional-Hazards Coefficients, Errors, and Relative Rates* From Multiple Regression Analyses of Ischemic Heart Disease According to Lipid, Lipoprotein, and Apolipoprotein Levels in the Cohort of 2155 Men

Fig 1 presents the Kaplan-Meier estimated survival probability across tertiles of apo B (top) and apo A-I (bottom). The log-rank test of equality across apo B strata was highly significant (P<.0005), suggesting that men in the third tertile of the apo B distribution showed a significant reduction in the probability of remaining free of IHD during follow-up compared with men in the first tertile. The survival probabilities among tertiles of apo A-I were not statistically different (P>.3), suggesting that apo A-I may not adequately predict IHD onset in this population of men.

View larger version (22K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival analysis across tertiles of apolipoprotein (apo) B and A-I levels expressed as the estimated probability for not having ischemic heart disease during the 5-year follow-up. Solid, dashed, and dotted lines represent the first, second, and third tertiles of apolipoprotein concentrations, respectively. The log-rank test showed that the difference in estimated probability was different over the three apo B tertiles (P<.0005) but not over the apo A-I tertiles (P>.3).

Multiple proportional-hazards models were used to study whether the association between apo B and A-I levels and incidence rate of IHD was modified by controlling for concomitant variations in selected plasma lipid and lipoprotein levels (Table 3). Controlling for triglycerides or HDL cholesterol did not substantially attenuate the relationship between apo B levels and incidence rate of IHD (RR for apo B, 1.48 and 1.40 after control for triglycerides and HDL cholesterol, respectively, P<.001). Because of the collinearity between cholesterol, LDL cholesterol, and apo B levels, these variables could not be simultaneously entered into one model. However, controlling for the ratio of total to HDL cholesterol did not eliminate the association between apo B and IHD. Indeed, the RR of IHD associated with changes in apo B levels remained significant after adjustment for the total/HDL cholesterol ratio (RR=1.29; 95% CI, 1.04 to 1.60). Controlling for HDL cholesterol or for the total/HDL cholesterol ratio completely eliminated what was an already weak association between apo A-I levels and the risk of IHD (RR=0.98 and 0.97, respectively, P=NS). The diagnosis of collinearity between HDL cholesterol and apo A-I levels obtained by multiple regression analysis was negative (R²=41% between these two variables). Finally, results presented in Table 3 indicate that apo B was a better predictor of IHD than apo A-I levels.

View this table: [in this window] [in a new window]   Table 3. Five-Year Relative Rates of Ischemic Heart Disease According to Apolipoprotein B and A-I Levels After Control for Concomitant Variations in Selected Plasma Lipid Levels

Table 4 summarizes the results of the stepwise proportional-hazards analysis. The first model confirmed the importance of the total/HDL cholesterol ratio in the prediction of IHD and also of LDL cholesterol levels, a finding concordant with previous epidemiological studies.^{1 2 34} In a second model, apo A-I and apo B levels were added to variables of the first model, whereas LDL was excluded from this analysis. Apo B was the only metabolic variable that remained in this model. This resulted in the exclusion of the total/HDL cholesterol ratio from the final model, suggesting that apo B was more strongly associated with IHD than the total/HDL cholesterol ratio in this cohort of men.

View this table: [in this window] [in a new window]   Table 4. Stepwise Analysis for the Prediction of Ischemic Heart Disease in the Cohort of 2155 Men From the Quebec Cardiovascular Study

Fig 2 examines the synergistic effects of the total/HDL cholesterol ratio and of apo B levels on the risk of IHD. Men with elevated apo B levels (above the 50th percentile of apo B distribution) but with a reduced total/HDL cholesterol ratio (below the 50th percentile of the distribution) showed a 60% increase in the RR of IHD (RR=1.6), but this difference did not reach statistical significance (95% CI, 0.8 to 3.0). Elevation in the total/HDL cholesterol ratio was associated with a higher risk of IHD, irrespective of apo B concentrations. However, among men with a high total/HDL cholesterol ratio, those with high plasma apo B levels were characterized by the highest increase in RR of IHD (RR=2.6; 95% CI, 1.6 to 4.1). Tests for interaction revealed no additive interaction between apo B levels and the total/HDL cholesterol ratio.

View larger version (52K): [in this window] [in a new window]   Figure 2. Synergistic effects of apolipoprotein (apo) B levels and the total/HDL cholesterol ratio on the relative rate of ischemic heart disease for men with values below and above the median for the total/HDL cholesterol ratio and apo B levels. The median value for the total/HDL cholesterol ratio was 5.65 and for apo B, 116 mg/dL. Relative rates were adjusted for confounders. *P<.07, **P<.001.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Apo B synthesis is required for the hepatic secretion of VLDL, and apo B remains associated with the particle during the triglyceride hydrolysis and lipid exchange cascade until its clearance from the circulation as IDL or LDL particles.³⁵ Measuring apo B in plasma is roughly equivalent to quantifying the number of apo B–containing lipoproteins secreted by the liver, because there is systematically only one apo B molecule per particle secreted. On the other hand, the cholesterol content of apo B–containing lipoproteins may be highly variable. Thus, for a given cholesterol concentration, a high number of apo B–containing lipoproteins will result in the presence of an elevated number of small, dense LDL particles, which have been associated with an enhanced risk of IHD.³⁶ Patients with IHD may be characterized by increased transport rates of LDL apo B,³⁷ even in the absence of hypercholesterolemia. They may also display an increased secretion of VLDL apo B particles, despite an apparently normal hepatic triglyceride synthesis,³⁸ a condition that may favor the formation of small, dense, atherogenic LDL particles.^{36 39}

There is an abundance of evidence from case-control reports to support the role of apo B as an important risk factor for IHD.^{9 13 14 15 16} The prospective data, however, are sparse and mostly inconsistent. Only four prospective studies have investigated the potential relationship between apo B levels and the risk of IHD in men.^{7 17 18 19} One study reported that coronary patients had plasma apo B values similar to those of control subjects.¹⁷ In the Physicians' Health Study,⁷ in which measurements of blood lipid and apolipoprotein levels were not performed while patients were in a fasting state, plasma apo B levels were correlated with IHD, but the association was not independent of the total/HDL cholesterol ratio. In a prospective study of men in Iceland,¹⁹ apo B was associated with myocardial infarction in the univariate analyses, but total cholesterol was a better discriminant in the multivariate analyses. In contrast, prospective data from the British United Provident Association Study showed that apo B was most strongly associated with IHD even after adjustment for total cholesterol and triglyceride levels in the multivariate analyses.¹⁸

These aforementioned studies, although prospective in design, nevertheless used a "case-control" approach. In the present population-based study, lipid and apolipoprotein measurements were performed on fresh plasma obtained at entry from all participants initially free of IHD. Results clearly indicated that elevated apo B levels were strongly associated with an increased RR of IHD. The discriminating power of apo B in the estimation of IHD risk remained significant after adjustment for triglycerides and HDL cholesterol, and among these variables, apo B came out as the strongest correlate of IHD in stepwise logistic analyses. Apo B should therefore be considered an important marker of IHD compared with conventional lipid variables, since it may provide additional and independent information on the risk of IHD. The number of IHD events reported here is likely to be an underestimation of the actual incidence of IHD, because only typical presentations of IHD events were considered, and atypical presentations such as silent myocardial infarction were not taken into account. Whether or not this issue may have influenced the relationship between risk factors and the development of IHD remains to be established. However, this situation is not peculiar to the Quebec Cardiovascular Study; several other prospective studies have confronted this situation.

It has been suggested that plasma apo A-I measurements may provide more information than HDL cholesterol levels in the assessment of IHD risk in men,^{8 40 41} but results available do not, in general, support this notion.^{7 15 17 19 34} Of the three prospective studies that have measured apo A-I and HDL cholesterol levels, all have concluded that apo A-I was not superior to HDL in predicting the risk of IHD.^{7 18 42} The ratio of apo B to apo A-I has also been suggested to be a more accurate predictor of the severity of IHD.¹⁵ In our study, men who developed IHD tended to have lower apo A-I levels compared with men who remained free of IHD, but neither apo A-I nor the apo B/A-I ratio (not shown) contributed to IHD risk after control for other lipids. These results suggest that apo A-I measurements, although potentially useful from a metabolic and therapeutic point of view, may not be an adequate variable for the screening of common dyslipidemias increasing the risk of IHD.⁴³

Lipoprotein-to-lipid ratios, such as LDL/HDL cholesterol and total/HDL cholesterol, are widely used to estimate IHD risk.^{4 6 34} In the Physicians' Health Study, the total/HDL cholesterol ratio was a strong predictor of IHD over a 5-year follow-up period after control for age and other risk factors such as history of angina, obesity, hypertension, and diabetes.⁷ From a statistical standpoint, results of the present prospective study suggest that apo B is a better predictor of IHD than the total/HDL cholesterol ratio, and among men with an elevated ratio, those with high plasma apo B levels showed the highest RR of IHD (Fig 2). From a therapeutic perspective, the use of such a ratio, as opposed to apo B, may not adequately reflect the effects of lipid-lowering therapy, because the lack of change in the ratio may be the result of parallel changes in both of its components. We have previously reported that hypertriglyceridemic men with normal apo B levels were not at increased risk for IHD, whereas hypertriglyceridemic men with elevated apo B levels were characterized by a threefold increase in risk of IHD.²⁴ Thus, while plasma apo B may identify a group of subjects who should not be treated, assessment of apo B levels may also be useful in the evaluation of response to lipid-lowering therapy,⁴⁴ especially in cases in which plasma lipid levels are marginally altered by treatment. The study by Brown et al⁴⁴ clearly indicated that intensive lipid-lowering therapy targeted to patients with elevated apo B levels not only diminished the rate of progression of coronary artery disease but also induced a net regression in angiographically determined coronary lesions.

Whether the measurement of apo B substantially improves our ability to identify individuals at risk for IHD compared with the use of the usual cholesterol indices still remains to be established. Indeed, the superiority of apo B over the total/HDL cholesterol ratio in predicting IHD appeared to be only modest. Although the measurement of plasma apo B concentrations has recently been standardized,⁴⁵ additional prospective studies are clearly warranted to justify its use for the assessment of IHD risk on a population basis. Other reports have suggested that an elevated total/HDL cholesterol ratio, besides serving as a relatively accurate marker for obstructive coronary disease, may also reflect the presence of a cluster of other risk factors.³⁴ Individuals with an elevated total/HDL cholesterol ratio have been characterized by hypertriglyceridemia, a tendency toward high hemoglobin and fibrinogen levels, and a history of smoking and previous myocardial infarction.³⁴ Although this ratio provides rather simple information on lipid abnormalities, it may also have the advantage of crudely describing a cluster of metabolic functions⁴⁶ through usual lipid measurements that are already applied in current clinical laboratory practice.

	Acknowledgments

 
This study was supported by the National Health Research Development Program of Health and Welfare Canada and by the Heart and Stroke Foundation of Canada. Benoit Lamarche is a recipient of a fellowship from the Medical Research Council of Canada. The financial contribution of Fournier Pharma/Jouveinal is also gratefully acknowledged. We are grateful to Dr N. Michelle Robitaille for her important support in the data collection and to Sylvain Poirier for his excellent collaboration with data analysis. The contribution of Louise Fleury is also gratefully acknowledged. We also thank the 4637 participants whose cooperation has made this study possible.

	Footnotes

 
Dr Moorjani died October 1, 1995. This article is dedicated to his memory.

Received December 4, 1995; revision received January 22, 1996; accepted January 22, 1996.

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