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1 Departments of Physiology and Physical Medicine, Rehabilitation and Sports Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico 00936; 2 Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808 - 4124; 3 Physical Activity Sciences Laboratory, Laval University, Québec, Canada G1K 7P4; 4 Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri 63110; 5 School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, Minnesota 55455; 6 Department of Kinesiology, Indiana University, Bloomington, Indiana 47405; and 7 Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843 - 4243
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the
association between an angiogenin gene polymorphism and blood pressure
(BP) at rest and in response to acute exercise before and after a 20-wk
endurance-training program. Subjects were 737 normotensive and
borderline hypertensive subjects (257 black and 480 white). The
polymorphism was detected by PCR and digestion with AvaII,
yielding an allele of 253 bp or a rare allele of 194 + 59 bp.
Resting and exercise [50 W; 60, 80, and 100% of maximal
O2 consumption (
O2 max)]
systolic (SBP) and diastolic BP were determined before and after
training. Among blacks, adjusted SBP in the sedentary state was
significantly lower in carriers of the rare allele at rest and exercise
intensities of 60, 80, and 100% of
O2 max. In the trained state, carriers
of the rare allele had a significantly (P < 0.05)
lower SBP than did noncarriers at rest and at 80 and 100% of
O2 max. The genotypic effect observed
among blacks was not evident among whites. Furthermore, change in BP
(after 
before) was not significantly associated with the
genotype. In conclusion, the angiogenin gene AvaII
polymorphism is associated with a lower SBP at rest and in response to
acute high-intensity exercise in blacks but not in whites.
genetics; AvaII; African Americans; acute exercise; endurance exercise
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE REGULATION OF BLOOD PRESSURE (BP) is influenced by several environmental and genetic factors (5). In North America, marked differences between individuals of African and European descent have been noted in the prevalence of hypertension and pathophysiological conditions related to it (7). Incidence of hypertension among those of African descent is at least twice that of those of European descent for nearly every age- and gender-matched group (6). Using the candidate gene approach, molecular studies have identified several genes influencing BP dynamics (5, 16). However, few data are available regarding the molecular mechanisms underlying BP dynamics in acute or chronic response to exercise. One of the main aims of the HERITAGE Family Study is to perform association and linkage studies between a panel of candidate genes and their possible relation to cardiovascular and metabolic responses to aerobic exercise training (4).
Chromosomal regions showing suggestive linkages with systolic BP (SBP) at rest and in acute response to exercise in the sedentary state as well as its adaptation to endurance training were observed in a recent genome-wide scan in the HERITAGE Family Study (unpublished observations). Among these chromosomal regions was the one enclosing marker D14S283, which is just 3 Mb upstream from the locus of a 14-kDa plasma protein known as angiogenin (ANG). ANG is a very effective inducer of neovascularization and has a high degree of homology with the primary sequence of the RNase A superfamily (22). In fact, it has a distinct, although weak, RNase activity (19). The gene encoding human ANG is located on chromosome 14, region q11 (26). This gene extends over 4,688 bp and lacks introns (10). Messenger RNA for ANG is expressed in a wide range of tumoral and normal human tissues (15), and the protein is present in plasma at concentrations of 250-360 µg/l (20).
The development of vascular networks, angiogenesis, is a key factor that influences individual variability in peripheral resistance and BP. It has been demonstrated that differences in capillarization are associated with inherited predisposition for BP abnormalities (12). Along these lines, skin and muscle capillary densities have been shown to be significantly lower in hypertensive subjects compared with normotensive controls (2, 8). This suggests that there are genetic mechanisms underlying angiogenesis that could reflect in BP control.
Because of its constant presence in plasma, it has been suggested that
ANG may have other functions besides that of angiogenesis. For example,
ANG has been suggested to be part of the host-defense system because of
its activity as a tRNase (18). In addition, it has been
demonstrated that ANG can promote the secretion of PGI2
(prostacyclin), a known vasodilator (3). Therefore, ANG could be involved in the regulation of BP, either by affecting the
body's capillary network (vascularization) or indirectly by stimulating the release of a vasodilating agent. Hence, it seems to be
a reasonable candidate gene to investigate in relation to BP dynamics.
The present study examined the hypothesis of an association between an
ANG gene polymorphism and BP at rest and in response to acute exercise
in the sedentary state, as well as its adaptation [change (
)] to
the endurance-training program of the HERITAGE Family Study
(4).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
The aims, design, and measurement protocol of the HERITAGE Family Study
have been described (4). The present study is based on
data from 737 (257 blacks and 480 whites) normotensive and borderline
hypertensive individuals. Subjects met a series of inclusion criteria
including SBP <160 mmHg and diastolic BP (DBP) 
99 mmHg. The study
protocol was previously approved by each of the Institutional Review
Boards of the HERITAGE Family Study research consortium. Written
informed consent was obtained from each participant. Mean age and
physical characteristics of the subjects are presented in Table
1.
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BP and exercise test methodology. BP measures were taken in the morning with the use of the Colin STBP-780 automated BP unit (San Antonio, TX) as described earlier (4). Proper cuff size (child, regular adult, or large adult) was determined by using recent guidelines (11). Subjects were seated in a reclining chair in a semirecumbent position. The laboratory was quiet, with little light and a room temperature between 23 and 26°C. After a rest period of at least 5 min, four BP readings were taken at 2-min intervals. The retained BP was the mean of three valid measurements. Subjects reported to the laboratory on a second day, within ±2 h of the time of the first day, and the same procedures were repeated.
Subjects completed a total of three exercise tests, each on a different day, both before and after training: a maximal test (Max), a submaximal test (Submax), and a Submax to Max test (Submax/Max) (21). All exercise tests were conducted on a cycle ergometer (SensorMedics Ergo-Metrics 800S, Yorba Linda, CA). Subjects completed the initial Max exercise test using a graded exercise test protocol, starting at 50 W for 3 min. The rate of work was then increased by 25 W every 2 min thereafter to the point of exhaustion. With the use of the results of this initial Max test, subjects then performed the Submax test on a second day, exercising at 50 W and 60% of their initial maximal O2 consumption (O2 max). Subjects exercised for ~12 min at each work rate, with a 4-min period
of seated rest between work rates. The Submax/Max exercise test was
then performed on a third day, starting with the Submax protocol, i.e.,
50 W and 60% of the initial O2 max,
and progressing to 80% of O2 max for 3 min and maximal level of exertion
(O2 max).
During the Submax and Submax/Max tests, BP values were obtained at 50 W
and at 60% of the initial O2 max,
whereas peak BP was obtained at the very end of the Max and Submax/Max tests. The values used in this paper are the means of the results obtained during the two Submax tests (Submax and Submax/Max) and for
the two Max tests (Submax/Max and Max) before and after the training
program. BP at 80% of initial O2 max
was obtained during the Submax/Max test. For all exercise tests,
O2 consumption, CO2 production, expiratory
minute ventilation, and the respiratory exchange ratio were determined
every 20 s and reported as a rolling average of the three most
recent 20-s values using a SensorMedics 2900 metabolic measurement
cart. O2 max was defined as the peak
value obtained during the test. Heart rate was determined by
electrocardiogram and the Colin STBP-780 instrument, and values were
recorded 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/Max tests. Further details concerning BP and
exercise test methodology can be obtained from recent publications (21, 27).
Endurance exercise training program. Participants trained under supervision were required to complete 60 training sessions within 21 wk. They could not exercise for more than one session/day, more than four sessions/week, or less than one session/week. In addition, they could not get ahead by more than two sessions or fall behind by more than two sessions. Participants who knew they might miss a few sessions were encouraged to train four times/week for 2 wk to build up a reserve. Program adherence was monitored several times per week. Participants were contacted when they appeared to be falling behind, and a plan was then developed to bring them back on schedule as soon as possible. Only subjects who completed at least 57 sessions (>95% of target) were kept for the present study.
Briefly, subjects exercised following a standardized protocol that required the use of a cycle ergometer (Universal Aerobicycle IV, Cedar Rapids, IA) in the sitting position. The cycle ergometer was connected to a computer system (Universal Mednet, Cedar Rapids, IA) that adjusted the power output of the ergometers to maintain constant training heart rates. During the initial 2 wk, subjects trained at a heart rate associated with 55% of each subject'sO2 max for 30 min/session. This was
gradually increased to 50 min by the end of the 14th wk at the heart
rate associated with 75% of O2 max.
These levels of intensity and duration were maintained through the
remaining 6 wk. Further details concerning the training program can be
found in previous publications (21, 27).
Genotype determinations.
DNA was extracted from lymphoblastoid cell lines after digestion by
proteinase K and purification with phenol-chloroform. The PCR
amplification targeted a region (1,944-2,196 bp) in codon 86, which includes the polymorphic site at 2,138 bp (T 
G). The primers
were as follows: 5'-GAT-GAC-AGA-TAC-TGT-GAA-AGC-ATC-3' (sense) and
5'-CAA-CAA-CAA-CGT-TTC-TGA-ACC-C-3' (antisense). A product of 253 bp
was obtained. The PCR reaction mixture and amplification protocols have
been described previously (14).
X174 DNA, digested with
HaeIII, was used as length marker to estimate the size of
the digested DNA fragments. The allele without the mutation (wild type)
was designated as the T allele, whereas the allele with the cutting
site (194 + 59 bp) was designated as the G allele.
Statistical analysis.
A 
2 test was used to examine gender differences in
allele and genotype frequencies and to determine whether the observed
genotype frequencies were in Hardy-Weinberg equilibrium. Associations
between BP phenotypes and the genetic marker were tested with analysis of covariance by using the general linear model procedure of the SAS
package (SAS Institute, Cary, NC) for personal computer (version 6.08)
(17). Baseline phenotypes were adjusted for age, gender, and body mass index (BMI), whereas posttraining values were adjusted for age, gender, and posttraining BMI. Training response (BP = pretraining posttraining) was adjusted for age, gender,
baseline BMI, and baseline value of the phenotypes. Possible
generation-by-genotype interaction effects were tested by introducing
an interaction term in the general linear model in addition to the
genotype and generation main effects. If the interaction term was
significant, association analyses were performed separately in parents
and offspring. In addition to the fully adjusted models, analyses were
also performed without adjustment, by adjusting for each of the
covariates separately and by using various combinations of covariates.
The results of all of these analyses were globally identical to those
of the full model, and, therefore, only the data from the full models
are reported in the present study.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The 2 analysis showed that neither allelic nor
genotype frequencies were significantly different between genders in
blacks or whites, respectively. In addition, no significant differences in allelic (0.93 and 0.07 vs. 0.89 and 0.11 for black men and women vs.
white; P = 0.34) or genotype frequencies
(P = 0.36) existed between races. The observed
genotypic frequencies for both races were in Hardy-Weinberg
equilibrium. Because of the low frequency of homozygotes for the rare G
allele (n = 1 in blacks; n = 3 in
whites) for each race, their data were pooled with those of
heterozygotes (T/G). Those two groups were designated as
"carriers," whereas homozygotes for the T allele were designated as
"noncarriers." Significant race-genotype interactions
(P < 0.05) were found at rest and at all exercise
intensities for sedentary-state SBP and at rest, 50 W, and 80 and 100%
O2 max in the trained state (Fig.
1). Because of these findings, data for
black and white subjects were analyzed separately.
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Figure 2 shows the sedentary-state SBP
for carriers and noncarriers of the rare G allele for black subjects.
Among this group of subjects, carriers of the rare allele had a
significantly (P < 0.05) lower sedentary-state SBP
than did noncarriers at rest and at 60, 80, and 100% of
O2 max. In the trained state (Table
2), black carriers of the rare allele had
a significantly (P < 0.05) lower SBP than did
noncarriers at rest and at 80 and 100% of
O2 max. Although there were no
significant associations at 50 W, significant gene-race interactions
were present in both the sedentary and trained state at this intensity.
This is illustrated in Fig. 1, where the lines corresponding to the
genotype effect in blacks and whites depart from parallelism.
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However, none of the significant genotypic effects observed in blacks
was evident in whites. Among white subjects, a significant (P = 0.04) difference between carriers and noncarriers
was evident only for sedentary-state DBP at 50 W (Table
3). In addition, the response (BP) to
the 20-wk endurance-training program was not significantly associated
with genotype in any group (data not shown).
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Comparison of white and black noncarriers in the sedentary and trained state showed that the former had significantly (P < 0.05) lower SBP and DBP at rest and at all exercise intensities. However, among carriers there was no significant difference in sedentary- or trained-state SBP at any of the exercise intensities tested. Nonetheless, in those subjects, significant differences in DBP persisted.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The existence of interactions between racial background and BP phenotype has been acknowledged for some time (1). However, information on how these racial differences relate to exercise and exercise training has been scarce. The present study utilized the candidate gene approach to investigate the association between a polymorphism in the human ANG gene and BP phenotypes at rest and at different intensities of exercise before and after a carefully standardized and monitored endurance-training program.
The main finding of this study was that, among black subjects, the
presence of the AvaII rare G allele was associated with a
lower SBP at rest and at exercise intensities of 60, 80, and 100% of
O2 max compared with the noncarriers.
The genotypic effect was present in both the sedentary state and after
a 20-wk cardiorespiratory endurance-training program. To our knowledge, the AvaII marker is the only restriction fragment-length
polymorphism reported so far for the ANG gene. The present marker is a
silent transversion (T G) present at the third position in codon
+86 and does not alter the encoded amino acid (26). Yet
the AvaII restriction fragment-length polymorphism
could be in linkage disequilibrium with more meaningful mutations in
the ANG gene (or perhaps another gene), and the results may have
implications far beyond the specific polymorphism considered here.
It is noteworthy that no genotypic effect was observed among white subjects. Furthermore, black noncarriers had significantly higher sedentary-state and trained-state SBP than did whites at rest and during exercise. However, when mean SBP of carriers was compared, these racial differences were no longer detectable. Therefore, the mutation is associated in blacks with a lower sedentary-state SBP, which results in a SBP similar to that of whites.
ANG is a potent angiogenic agent in biological assays and is synthesized in normal and tumoral tissues (23). In this context, it is possible that, among black subjects, the rare allele is a marker of greater vascularization of skin, cardiac, and/or skeletal muscle. Because the microcirculation is a key site of vascular resistance control, greater vascularization could translate into a greater capacity to handle increased peripheral blood flow, and, therefore, a lower BP at rest and in response to exercise may be expected. This latter assumption is supported by the significant differences in SBP between carriers and noncarriers observed not only through moderate-to-maximal exercise, but also at rest when vasodilating mechanisms are not necessarily active.
Although increases in muscle capillary density are known to occur in
response to endurance exercise training (9), in the present study there was no significant association between ANG AvaII genotype and BP. The fact that significant
differences in SBP between ANG genotypes were present, both in the
sedentary and trained state, seems to suggest that this is a marker for vascularization as an inherited and life-long characteristic and may
not necessarily interact with training. In agreement with this, it has
been observed that defective angiogenesis is associated with inherited
propensity for the development of hypertension (12).
On the other hand, ANG could affect other mechanisms related to BP
regulation. For instance, it has been demonstrated that ANG can promote
the secretion of PGI2 from endothelial cells
(3). PGI2 is known to exert a relaxant effect
on coronary, pulmonary, cerebral, mesenteric, and renal vascular tone,
thus lowering BP. Interestingly, it has been shown that infusion of
PGI2 alters BP differentially, depending on the dose. The
lowering effect is seen predominantly on SBP and to a lesser degree on
DBP when doses of 20 ng · kg
1 · min1 or more are
infused (24). Thus it may be speculated that significant differences seen here in SBP but not in DBP could be the result of the
vasodilatory capacity of PGI2 at high concentrations.
Although PGI2 has been observed to increase in response to
acute strenuous exercise, no significant differences in circulating
concentrations of PGI2 existed between endurance athletes
and sedentary controls (25). Thus it has been suggested
that the elevation in the concentration of PGI2 during
acute strenuous exercise is a normal physiological response and does
not necessarily change with training. This is consistent with the lack
of difference in BP between ANG genotypes in the present study.
In summary, the results demonstrate that, among blacks, a significant
association exists between a polymorphism of the ANG gene and SBP at
rest and during exercise in both the sedentary and trained states.
Carriers of the rare G allele showed significantly lower SBP at rest
and during exercise intensities of 60, 80, and 100% of
O2 max. The genotype effect was not
evident in the SBP response () to the endurance-training program in
any of the groups. Furthermore, none of the genotype effects observed in blacks was detected among white subjects. The significant
association between the ANG locus and the SBP phenotypes indicates that
the ANG gene, or a gene in linkage disequilibrium with it, may be responsible for the observed differences. Further research is necessary
to establish the true nature of this association. Differences in skin,
cardiac, or muscle vascularization or in PGI2-mediated vasodilation should be considered as possible mediators.
In conclusion, the observed interaction between race and the ANG AvaII marker partially explains racial differences in BP at rest and in acute response to exercise in the sedentary and trained states. The significant association between genotype and BP phenotypes provides further insight into the genetic control of BP at rest and during exercise.
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ACKNOWLEDGEMENTS |
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Thanks are provided to all investigators, local project coordinators, research assistants, laboratory technicians, and secretaries who have contributed to this study.
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FOOTNOTES |
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The HERITAGE Family Study is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health through the following grants: HL-47323, HL-47317, HL-47327, HL-47321, and HL-45670. A. S. Leon is partially supported by the Henry L. Taylor Professorship in Exercise Science and Health Enhancement, and C. Bouchard is supported in part by the George A. Bray Chair in Nutrition.
Address for reprint requests and other correspondence: M. A. Rivera, Dept. of Physical Medicine, Rehabilitation and Sports Medicine, Univ. of Puerto Rico School of Medicine, Main Bldg. Office A-204, San Juan, Puerto Rico 00936 (E-mail: mirivera{at}rcm.upr.edu).
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. Section 1734 solely to indicate this fact.
Received 6 December 1999; accepted in final form 3 October 2000.
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REFERENCES |
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
REFERENCES
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)
and white (
) subjects of the HERITAGE Family Study.
Carriers, G allele homozygotes (GG) and heterozygotes (GT);
noncarriers, TT homozygotes. Values are means ± SE;
* Significant difference compared with white noncarriers,
P < 0.05; ns, nonsignificant compared with white carriers.
