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1 Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808-4124; 2 Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada G1K 7P4;3 School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, Minnesota 55455; 4 Department of Kinesiology, Indiana University, Bloomington, Indiana 11001; 5 Department of Health and Kinesiology, Texas A & M University, College Station, Texas 77843-4243; and 6 Division of Biostatistics and Departments of Genetics and Psychiatry, Washington University Medical School, St. Louis, Missouri 63110-1093
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been suggested that genetic
variation in the angiotensin-converting enzyme (ACE) gene is
associated with physical performance. We studied the
association between the ACE insertion (I)/deletion (D)
polymorphism and several fitness phenotypes measured before and after
20 wk of a standardized endurance training program in sedentary
Caucasian (n = 476) and black (n = 248)
subjects. Phenotypes measured were oxygen uptake
(
O2), work rate, heart
rate, minute ventilation, tidal volume, and blood lactate levels during
maximal and submaximal [50 W and at 60 and 80% of maximal
O2
(O2 max)] exercise and stroke volume and cardiac output during submaximal exercise (50 W and at 60%
O2 max).
The ACE ID polymorphism was typed with the three-primer PCR
method. Out of 216 association tests performed on 54 phenotypes in 4 groups of participants, only 11 showed significant (P values
from 0.042 to 0.0001) associations with the ACE ID
polymorphism. In contrast to previous claims, in Caucasian offspring,
the DD homozygotes showed a 14-38% greater increase with training
in O2 max,
O2 at 80% of
O2 max, and all work
rate phenotypes and a 36% greater decrease in heart rate at 50 W than
did the II homozygotes. No associations were evident in
Caucasian parents or black parents or offspring. Thus these data do not
support the hypothesis that the ACE ID polymorphism plays a
major role in cardiorespiratory endurance.
candidate gene; exercise training; responsiveness; insertion/deletion polymorphism
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A HIGH LEVEL OF AEROBIC FITNESS is an essential
requirement for success in endurance sports. In addition, several
studies have shown that a low level of cardiorespiratory endurance
is associated with an increased risk for several degenerative diseases (2, 10, 18, 19). Cardiorespiratory fitness, for which maximal oxygen
consumption (O2 max) is
traditionally recognized as the gold standard, is a multifactorial
phenotype influenced by several genetic and environmental factors.
Among the environmental factors, regular physical activity is the major
contributor to the
O2 max level. However,
several exercise training studies have shown that there are marked
interindividual differences in the trainability of cardiorespiratory
endurance phenotypes after exposure to an identical training program.
For example, after supervised training programs of 15-20 wk in 47 healthy young men, the training responses of
O2 max ranged
from almost no change to an increase of almost 1 liter (3). Similarly,
the improvements in total work output during a 90-min ergometer test
ranged from 16 to 97% after 20 wk of standardized endurance training
(22).
This individual variability in exercise responses has been described as
a normal biological phenomenon that may reflect genetic diversity (3).
Both twin and family studies support the hypothesis of a significant
genetic effect on
O2 max in the sedentary
state and other fitness phenotypes. The intrapair resemblance for
cardiorespiratory endurance phenotypes is significantly higher in
monozygotic twins than in dizygotic twins (7, 12, 23, 34), with
heritability estimates ranging from 25 to 66%. The data from the
family studies by using either measured (20) or estimated (21)
O2 max or both (25)
have suggested a genetic effect of ~25-40% after adjusting for
age, gender, and body mass or body composition. In the
HERITAGE Family Study cohort, a maximal heritability of 51% was
observed for the
O2 max
(adjusted for age, gender, and body composition) measured in the
sedentary state (5).
Because endurance performance is a multifactorial trait, the list of
candidate genes that could account for human variation in related
phenotypes is extensive. Thus far, associations between O2 max and genetic
variation in skeletal muscle-specific creatine kinase locus (4, 27) as
well as mitochondrial DNA sequence variations (9) have been described.
However, over the last 2 yr, significant associations between the
angiotensin-converting enzyme (ACE) insertion (I)/deletion (D)
polymorphism and performance-related phenotypes have been reported. In
78 British military recruits, an 11-times-greater training response in
repetitive elbow flexions with a 15-kg barbell was observed in the II
homozygotes than in the DD homozygotes after a 10-wk training period.
In the same paper, it was reported that the frequency of the D allele
was significantly lower in male mountaineers than in a random sample of
British men (24). Also, in Australian Olympic rowers, the frequencies
of the D allele and the DD genotype were lower than in nonathlete
controls (15). Finally, a higher
O2 max was reported in
postmenopausal women carrying the II genotype than in the DD
homozygotes (16). However, in a cohort of 192 endurance athletes with
O2 max >75
ml · kg
1 · min1
and 189 sedentary controls with
O2 max <50
ml · kg1 · min1,
collected by our laboratory in collaboration with European and United
States centers (the GENATHLETE project), no differences were found in
the distribution of the ACE ID genotypes between the groups
(26a). Further classification of the athletes on the basis of
O2 max did not provide
any evidence for an excess of the I allele or the II genotype among the
athletes with high
O2 max values (>83
ml · kg1 · min1).
ACE catalyzes the conversion of angiotensin I to angiotensin II and, therefore, is an integral part of the renin-angiotensin system. ACE also degrades vasodilatory substances such as bradykinin. Plasma ACE activity is strongly influenced by genetic factors, and the ID polymorphism in the intron 16 of the ACE gene seems to be a marker of another variant responsible for its regulation (26, 36). However, there is no physiological explanation for the ACE-fitness association reported in some studies. Moreover, frequencies of the ACE ID alleles and genotypes vary considerably across different ethnic groups (1, 13, 28), yet populations showing greater I allele frequencies are apparently not characterized by a higher performance level, which could represent circumstantial evidence against a role for this gene.
Although the observations by Montgomery et al. (24), Gayagay et al. (15), and Hagberg et al. (16) may seem quite consistent, problems with study designs, sample sizes, and performance phenotype measurements make the interpretation of these findings extremely difficult. Thus the purpose of this study was to evaluate the above hypothesis by analyzing the associations between the ACE ID genotype and various cardiorespiratory endurance-related phenotypes in the sedentary state and in response to 20 wk of endurance training in 476 Caucasian and 248 black adult subjects from the HERITAGE Family Study cohort.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. The study cohort consists of 476 Caucasian subjects (229 men and 247 women) from 99 families and 248 black subjects (88 men and 160 women) from 104 families. The study design and inclusion criteria have been described previously (6). To be eligible, the individuals were required to be in good health, i.e., free of diabetes, cardiovascular diseases, or other chronic diseases that would prevent their participation in an exercise training program. Subjects were also required to be sedentary, defined as not having engaged in regular physical activity over the previous 6 mo. Individuals with resting systolic blood pressure >159 mmHg and/or diastolic blood pressure >99 mmHg were excluded. The study protocol had been approved by each of the Institutional Review Boards of the HERITAGE Family Study research consortium. Written informed consent was obtained from each participant.
Exercise training program.
The exercise intensity of the 20-wk training program was customized for
each participant on the basis of the heart rate (HR)-oxygen consumption
(O2) relationship measured
at baseline. During the first 2 wk, the subjects trained at a HR
corresponding to 55% of the baseline
O2 max for 30 min/session. Duration and intensity of the training sessions were
gradually increased to 50 min and 75% of the HR associated with
baseline O2 max,
which were then sustained for the last 6 wk. Training frequency was
three times per week, and all training was performed on cycle
ergometers in the laboratory. HR was monitored during all training
sessions by a computerized cycle ergometer system (Universal FitNet
System), which adjusted ergometer resistance to maintain the target HR. All exercise sessions were supervised by trained exercise specialists.
Fitness phenotypes.
Before and after the 20-wk training program, each subject completed
three cycle ergometer (SensorMedics Ergo-Metrics 800S, Yorba
Linda, CA) exercise tests conducted on separate days: a maximal
exercise test (Max), a submaximal exercise test (Submax), and a
submaximal/maximal exercise test (Submax/Max). The Max test started at
50 W for 3 min, and the power output was increased by 25 W every 2 min
thereafter to the point of exhaustion. For older, smaller, or less-fit
subjects, the test was started at 40 W and increased by 10- to 20-W
increments. On the basis of the results of the Max test, the Submax
test was performed at 50 W and at 60% of the initial
O2 max. Finally, the
Submax/Max test was started with the Submax protocol and progressed to
a maximal level of exertion. During the Submax/Max test, blood samples were obtained via a venous catheter at rest; during exercise at 50 W,
60% of O2 max, 80%
of O2 max; and
immediately on completion of Max test; and blood lactate concentrations
were determined after deproteinization by using an enzymatic procedure
(Sigma Diagnostics, St. Louis, MO). During the Submax and Submax/Max tests, subjects exercised for 9-12 min at each work rate, with a
4-min period of seated rest between exercise periods.
O2 ,carbon
dioxide production, expiratory minute ventilation
(E), and tidal volume (VT)
were determined every 20 s and reported as a rolling average of the
three most recent 20-s values. All the respiratory phenotypes were
measured by using a SensorMedics 2900 metabolic measurement cart.
O2 max was defined as
the mean of the highest O2
values determined on each of the Max tests or the higher of the two
values if they differed by >5%. HR was recorded by
electrocardiography, and values were obtained during the last 15 s of
each stage of the Max test and once steady state had been achieved at
each of the submaximal work rates during the Submax and Submax/Max
tests. Cardiac output was determined twice at 50 W and 60% of
O2 max by using the Collier CO2 rebreathing technique (8), as described by
Wilmore et al. (38). A mean of the two measurements was used for the analyses.
Other phenotypes. Stature was measured to the nearest 0.1 cm with the subject standing erect on a flat surface, heels, buttocks and back pressed against the stadiometer, and the head positioned in the Frankfort horizontal plane. Body mass was recorded to the nearest 100 g by using a balance scale with subjects clothed only in a lightweight bathing suit. Body mass index was calculated by dividing body mass (kg) by stature squared (m2).
Genotype determinations. Genomic DNA was isolated from lymphoblastoid cell lines following a standard protocol (29). The ACE ID polymorphism was typed with a PCR-based method using three primers as previously described (11). The final reaction mixture of 15 µl contained 100 ng of genomic DNA, 3.0 mM MgCl2, 200 µM each 2'-deoxynucleoside 5'-triphosphate, 300 nM primers flanking the insertion sequence, 140 nM nested primer, 4.7% DMSO, and 1.0 U of Taq polymerase (Pharmacia Biotech, Baie d'Urfé, PQ, Canada). The PCR protocol (model 9600 thermal cycler, Perkin Elmer, Norwalk, CT) consisted of one cycle at 94°C for 3 min, 55°C for 1 min, and 72°C for 1 min, followed by 35 cycles at 94°C for 30 s, 55°C for 30 s, 72°C for 45 s, and finally one cycle at 72°C for 10 min. The PCR products were separated on 3.5% agarose gel and visualized under ultraviolet light after ethidium bromide staining.
Statistical analyses. A X2 test was used to confirm that the observed genotype frequencies were in a Hardy-Weinberg equilibrium. The normality of the distributions was checked with the Shapiro-Wilk statistic of the UNIVARIATE procedure of the SAS statistical software package (SAS Institute, Cary, NC). Skewed distributions were normalized with logarithmic transformations. The associations between fitness phenotypes and the genetic markers were tested with analysis of covariance by using the general linear model procedure of the SAS package. Baseline phenotypes were adjusted for age, gender, and body weight and training response phenotypes for age, gender, baseline body weight, and baseline value of the given phenotype. The results are given as means and SD for the unadjusted variables and as means and SE for the adjusted variables.
All the family members were included in the analyses. Although it is commonly believed that the relatedness of the subjects in family study cohorts may cause problems in association analyses, a recent simulation study (M. Province, T. Rice, and D. C. Rao, unpublished observations) suggests that this is not the case. In that study, the data were analyzed by four methods, where the least squares method used in the present report was one of them; the other three methods treated dependencies in different ways. The results show that, first, failure to incorporate dependencies did not induce any bias and that, second, for moderate familial correlations as seen in most family studies (including the present one), ignoring the dependencies by using ANOVA performed quite well. The only negative impact was a small reduction in power. The SEs were slightly enlarged but, most importantly type I error was unaffected. Given this, we do not believe that the dependencies or relatedness of the subjects in families causes any real problems in this type of analysis. To explore thoroughly the associations between the ACE ID polymorphism and cardiorespiratory endurance traits, we selected a large number of phenotypes representing its cardiovascular, respiratory, and metabolic aspects. However, to facilitate the reporting and interpreting of the results, the phenotypes were divided into two groups: the primary (O2 and HR at 50 W, 60 and
80% of O2 max, and
at maximal exercise; work rate at 60% and 80% of
O2 max, and at
maximal exercise) and the secondary (cardiac output and stroke volume
at 50 W and 60% of
O2 max, E, VT, and blood lactate
levels at 50 W, 60% and 80% of
O2 max, and at
maximal exercise) phenotypes. Thus altogether 11 primary and 16 secondary phenotypes, both in the sedentary state and for the
training response, were analyzed. Although the number of phenotypes tested is large, we did not make any adjustment for multiple testing because the purpose of the study is to explore the possible
ACE-cardiorespiratory endurance associations, and we believe that for
this purpose it is more informative to report all the actual results.
However, we do recognize the issue of multiple testing and it has been taken into consideration in the interpretation of the results.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The baseline characteristics of the subjects are presented in Table
1. The exercise training program increased
O2 max by 16.7 ± (SD)
9.4, 17.0 ± 8.9, 22.6 ± 11.3, and 17.4 ± 8.9 % and increased
maximal work rate by 28.6 ± 14.7, 28.5 ± 13.4, 36.1 ± 25.3, and
30.9 ± 15.0% in Caucasian parents, Caucasian offspring, black
parents, and black offspring, respectively. The frequencies of the
insertion and deletion alleles of the ACE marker were 0.468 and
0.532 in Caucasian subjects and were 0.416 and 0.584 in black subjects.
In both races, the genotype frequencies were in a Hardy-Weinberg equilibrium.
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The associations between baseline cardiorespiratory endurance
phenotypes and the ACE ID genotypes are summarized in Tables 2 and 3. None
of the primary fitness phenotypes were associated with the ACE
ID polymorphism in Caucasians. In black parents, baseline
HR at 60 and 80% of
O2 max showed a
significant association with the ACE marker, but the
significance was due to the higher values seen in the ID heterozygotes
than in the II and DD homozygotes. Of the secondary fitness phenotypes,
only baseline lactate levels at 60 and 80% of
O2 max workloads were
associated with the ACE ID polymorphism in the Caucasian
offspring but not in other subgroups. The DD homozygotes showed
significantly lower blood lactate levels at both submaximal exercise
workloads than in the other genotypes (Fig.
1). Lactate levels measured at 50 W or at
maximal exercise were not associated with the ACE ID
polymorphism.
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The responses to the 20-wk exercise training program of
the primary cardiorespiratory endurance phenotypes were similar across the ACE ID genotypes in Caucasian and black parents and in black offspring (Tables 4 and
5). In Caucasian offspring, the DD
homozygotes showed the greatest increases in
O2 max,
O2 at 80% of
O2 max, maximal work
rate, and work rate at 80 and 60% of
O2 max and the greatest
decreases in HR at 50 W (P values from 0.042 to 0.0001, adjusted for age, gender, baseline body mass, and baseline value of the
phenotype). Of the secondary fitness phenotypes, the ventilation phenotypes showed some associations with the ACE ID marker
(data not shown). In Caucasian offspring, the DD homozygotes showed a
greater (P = 0.032) increase in
E 60 (+4.2 ± 0.6 l/min) than did the II
homozygotes (+1.9 ± 0.6 l/min) and the ID heterozygotes (+3.0 ± 0.6 l/min). Also the training response of VT at 60% of O2 max followed a
similar pattern (+0.12 ± 0.02, +0.05 ± 0.02 and +0.06 ± 0.02 liter in the DD, ID, and II genotypes, respectively; P = 0.036). In addition, the E at 80% of
O2 max training
response tended to be greater in the DD homozygotes (P = 0.063). In the Caucasian parents, the
E at
O2 max training
response was the greatest (P = 0.026) in the DD homozygotes
(+13.7 ± 1.3 vs. +8.6 ± 1.5 and 9.7 ± 1.2 l/min in the II and ID
genotypes, respectively). However, in black parents, the II homozygotes
had increase of 9.6 ± 2.5 l/min in E at
80% O2 max, whereas
the response of the DD and ID genotypes were +0.6 ± 1.6 and +6.0 ± 1.4 l/min, respectively (P = 0.007). Cardiac output, stroke
volume, and blood lactate training responses were not associated with
the ACE ID polymorphism.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Some previous studies have reported that the I allele of the ACE I/D polymorphism is associated with enhanced physical performance (15, 16, 24). However, the results of the present study, based on data from 476 Caucasian and 248 black subjects, do not support the earlier findings derived from considerably smaller cohorts. In the sedentary state, none of the cardiorespiratory endurance-related phenotypes were associated with the ACE ID polymorphism. Moreover, the associations between training responses and the ACE marker were seen only in Caucasian offspring. Furthermore, unlike previous reports, the homozygotes for the D allele showed the most favorable changes.
The results from the present study and those reported earlier are conflicting. However, differences in study designs and subject selection strategies, sample sizes, and measurements of phenotypes may explain most of the differences. First, the greater frequency of the I allele observed among the athletes in the case-control studies (15, 24) could be simply explained by a selection bias or a simple sampling problem. If the I allele is associated with a healthier cardiovascular system as some studies suggest (33), it is possible that the requirement of a healthy cardiovascular system for endurance sports favors the selection of the II homozygotes among endurance athletes. However, this is not supported by the data from the GENATHLETE project based on a much larger sample of athletes and matched controls (26a). The selection bias may also have affected the results derived from a cohort of British soldiers (24). The frequency of the I allele (0.551) among the male military recruits is significantly higher than that reported in other Caucasian populations (32), including the HERITAGE cohort (0.468).
The performance phenotypes used in the previous studies is another
factor hampering the interpretation of the results. The repetitive
elbow flexion test with a 15-kg barbell used by Montgomery et al. (24)
is not a standard test of physical performance. Because the authors did
not give any repeatability estimates for the test, it is difficult to
evaluate how reliable the results derived from this test are. In
addition, the elbow flexion test employs mainly the biceps, a fairly
small muscle group. Thus it is unclear whether this test is a valid
surrogate for skeletal muscle performance capacity or whether it has
any relationship with cardiorespiratory endurance. In the HERITAGE
Family Study, we paid close attention to the quality of the phenotype
measurements (14). For example, both maximal and submaximal
cardiorespiratory endurance phenotypes are derived from two separate
tests both before and after the training program. As reported
previously (30, 39), the intraclass correlation coefficients for
repeated measurements of the fitness phenotypes are high, ranging from 0.76 to 0.99. The coefficient for
O2 max reached 0.97 (30).
A common feature of the papers on the associations between the ACE ID polymorphism and performance phenotypes published so far is that the sample sizes have been relatively small, varying from 25 to 78. The present study, which is by far the intervention study with the largest sample size and the most rigorously controlled, and the GENATHLETE case-control study from our laboratory with 192 endurance athletes and 189 sedentary controls, both do not support the notion that the I allele is associated with greater performance capacity. In fact, a similar effect of sample size has been reported for the hypothesis of an increased cardiovascular disease risk associated with the D allele. Staessen and co-workers (33) reported in a meta-analysis of 49,959 subjects from 145 studies that the estimates of increased risk of coronary heart disease and nephropathy tend to decrease as a function of the sample size among these studies. Moreover, the results revealed a publication bias; i.e., smaller studies with negative findings were not reported in the literature (33). It is important to remember that a small sample size implies not only low statistical power but also a greater risk of spurious positive findings due to the contribution of outliers. Therefore, the replication of findings derived from small cohorts in studies with larger sample sizes is of the utmost importance.
At present, a physiological explanation for any association between the endurance-related cardiorespiratory phenotypes and the ACE polymorphism is missing. Although local renin-angiotensin systems (RAS) have been identified in several tissues, including skeletal muscle, it is unlikely that the effect of ACE is mediated by the RAS. There is no indication that an increased ACE activity per se leads to enhanced angiotensin II production. In fact, an increment in ACE activity associated with an increase in the number of functional ACE genes does not affect angiotensin II levels (31). However, the increased ACE activity in the DD homozygotes could have physiologically significant effects if the substrate delivery (angiotensinogen, angiotensin I, bradykinin) was also increased (35, 37). On the other hand, we cannot exclude the possibility that the putative effects of the ACE gene could be mediated independently of the RAS. ACE is able to degrade vasodilatory substances such as bradykinin, and the resulting impaired vasodilation in the ACE DD homozygotes may theoretically influence the peripheral circulation and thereby oxygen and substrate delivery to the working muscles. However, we believe that the findings of the present study do not provide support for this hypothesis. Finally, it is possible that some or all of the associations reported between physical performance and the ACE gene polymorphism could be due to linkage disequilibrium with other gene or genes in close proximity to the ACE locus and not to the ACE gene per se. One such potential candidate is the human growth hormone gene, which is located in vicinity of the ACE gene as shown by a close linkage and a lack of recombination with the ACE locus. (17).
In summary, these data from the HERITAGE Family Study do not support the concept that genetic variation at the ACE locus is a major contributor to the cardiorespiratory endurance-related phenotypes in the sedentary state or to their responses to regular and standardized endurance training in healthy Caucasian or black subjects.
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ACKNOWLEDGEMENTS |
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The HERITAGE Family Study is supported by National Heart, Lung, and Blood Institute Grants HL-45670 (to C. Bouchard), HL-47323 (to A. S. Leon), HL-47317 (to D. C. Rao), HL-47327 (to J. S. Skinner), and HL-047321 (to J. H. Wilmore). A. S. Leon is partially supported by the Henry L. Taylor endowed Professorship in Exercise Science and Health Enhancement. C. Bouchard is partially supported by the Donald B. Brown Research Chair on Obesity funded by the Medical Research Council of Canada and Hoffmann-La Roche Canada. T. Rankinen is a fellow from the Medical Research Council of Canada.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. Bouchard, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808-4124 (E-mail: BouchaC{at}pbrc.edu).
Received 12 May 1999; accepted in final form 9 November 1999.
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TOP
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METHODS
RESULTS
DISCUSSION
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