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1 gene-race interactions for
resting and exercise blood pressure in the HERITAGE Family
Study
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; 7 Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843-4243; and 8 Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the
possible association between a transforming growth factor
(TGF)-
1 gene polymorphism in codon 10 and blood pressure
(BP) at rest, in acute response to exercise in the pretrained (sedentary) and trained states, as well as in its training response (
) to 20 wk of endurance exercise. Subjects were 257 black and 480 white, healthy sedentary normotensive subjects from the HERITAGE Family
Study. The polymorphism was detected by polymerase chain reaction and
digestion with the Msp A1 I endonuclease yielding a wild
(leucine-10) and a mutant (proline-10) allele. Resting and exercise
[50 W plus 60, 80, and 100% maximal oxygen consumption (
O2 max)] BP were determined before
and after training. Significant (P < 0.05)
race-genotype interactions were found for systolic (S) BP in both the
sedentary and trained states. Among whites but not in blacks, the
TGF-1 genotypes were significantly (P < 0.05) associated with sedentary-state SBP at rest, at 50 W, and at 60 and 100% O2 max as well as with
trained-state SBP at rest and at 80 and 100%
O2 max. The leucine-10 homozygotes had
significantly (P < 0.05) lower SBP than proline-10 homozygotes. BP was not significantly associated with genotype. These results support the hypothesis of an association between the
TGF-1 marker in codon 10 and SBP at rest and in response to acute exercise in whites but not in blacks.
genetics; polymerase chain reaction; genetic variation; DNA; endurance; transforming growth factor-1
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WIDELY ACCEPTED
that blood pressure (BP) regulation is influenced by several
environmental and genetic factors (6). Genetic
epidemiology studies of BP indicate familial aggregation for both
resting systolic (S) and diastolic (D) BP (23, 36, 37),
with maximal heritability estimates ranging from 30 to 70% (6,
7, 15, 36). Regarding exercise BP, unpublished data from the
HERITAGE Family Study reveal maximal heritability estimates of
48-52% (A. S. Leon, P. An, T. Rice, L. Pérusse, J. Gagnon, J. H. Wilmore, J. S. Skinner, D. C. Rao, and C. Bouchard, unpublished observations). However, not much is known about
the actual molecular mechanisms underlying the physiological basis of
acute BP response to exercise or its chronic adaptation to endurance
exercise training. One of the main aims of the HERITAGE Family Study is
to study a panel of candidate genes and phenotypes of cardiovascular
and metabolic responses to aerobic exercise training (5).
The present report considers a candidate gene potentially related to
phenotypes of cardiovascular response to exercise: transforming growth
factor (TGF)-1.
TGF-1 is a multifunctional protein that plays
an important role in the modulation of cellular growth and
differentiation (13) and in the production and degradation
of extracellular matrix (ECM) proteins (24) in a wide
variety of cell types. It is initially synthesized as a 390-amino acid
precursor protein and then is secreted as a latent complex. This latent
complex can be activated by extreme pH, heat, or proteolytic enzymes
(14). The TGF-1 gene is encoded on
chromosome l9ql3.1-ql3.3 and displays seven exons (11,
14). TGF-1 has attracted attention because of its
possible role in cardiovascular pathophysiology (1, 8, 9, 12, 21,
34, 39) and target-organ complications of hypertension
(21, 26). Higher concentrations of circulating TGF-1 were observed in hypertensive compared with
normotensive subjects among both blacks and whites (33).
Similarly, significant and positive correlations between circulating
levels of TGF-1 and resting SBP, DBP, and mean arterial
pressure were observed in end-stage renal disease patients
(21). TGF-1 may influence BP by promoting
the deposition of ECM proteins on vessel walls, thereby affecting its
stiffness and compliance (24). TGF-1 may
also affect BP because of its ability to 1) stimulate the synthesis of the vasoconstrictor agent endothelin-1 (ET-1)
(19), 2) increase renin secretion
(4), and 3) inhibit the production of the
vasodilator nitric oxide (NO) (29).
Significant associations between various polymorphisms of the
TGF-1 gene and aspects related to BP regulation have
been shown. Among them, a DNA polymorphism in the 5' promoter region of
the TGF-1 gene (C-509T) has recently been shown to be
associated with plasma concentrations of the TGF-1
protein. In addition, a significant association between a
TGF-1 polymorphism in codon 25 (arginine 
proline)
and resting SBP of normotensive individuals has also been reported
(9). In that study, carriers of the rare proline-25 allele
had a resting SBP 5-10 mmHg lower than that of noncarriers.
Furthermore, another study found that, among hypertensive subjects,
there was a higher percentage of homozygotes for the arginine-25 allele
compared with normotensive subjects (21).
Another known polymorphism on the TGF-1 gene is found at
codon 10 (leucine proline) on the signal peptide region
(9). The heterozygosity index (H = 0.49) of this
polymorphism is greater than that of codon 25 (H = 0.15) making it
a more informative site. A previous study on this polymorphic site
reported a higher frequency of the proline-10 allele in whites than in
blacks (33). However, the authors did not look into a
possible association between genotypes for that locus and BP.
Therefore, the present study examined the hypothesis of an association
between the TGF-1 gene polymorphism in exon 1, codon 10 (leucine proline), and BP at rest and in response to acute exercise
in the sedentary and trained states, as well as in the training
response () to an endurance-training program in 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.
Details of the HERITAGE Family Study aims, experimental design, and
measurement protocols have been presented in detail in a previous
publication (5). The sample for the present study consists
of 737 (257 blacks and 480 whites) healthy, sedentary normotensive
subjects from 105 black and 99 white nuclear families. Subjects met a
series of inclusion criteria, including SBP of <160 mmHg and DBP of
99 mmHg. The study protocol had been previously approved by each of
the Institutional Review Boards of the HERITAGE Family Study research
consortium. Written, informed consent was obtained from each
participant. Race-specific values for the physical characteristics 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 (San Antonio, TX) STBP-780 automated BP unit as described earlier (5). Proper cuff size (child, regular adult, or large adult) was determined by using recent guidelines (17). 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 submaximal-to-maximal test (Submax/Max) (32). All exercise tests were conducted on a cycle ergometer (SensorMedics Ergo-Metrics 800S, Yorba Linda, CA). Subjects completed the initial Max by 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. By using the results of this initial Max, subjects then performed Submax on a second day exercising at 50 W and 60% of their initial maximal oxygen consumption (O2 max). Subjects exercised for ~12
min at each work rate, with a 4-min period of seated rest between work
rates. Submax/Max was then performed on a third day, starting with the
Submax protocol, i.e., 50 W and 60% of initial
O2 max, and progressing to 80% O2 max for 3-min and maximal level of
exertion (100% O2 max).
During the Submax and Submax/Max, BP values were obtained at 50 W and
at 60% of initial O2 max, whereas peak
BP was obtained at the very end of Max and Submax/Max. The values used in this paper are the mean of the results obtained during and for
Submax/Max and Max, before and also after the training program. BP at
80% of initial O2 max was obtained
during Submax/Max. For all exercise tests, oxygen production, carbon
dioxide 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 by using a SensorMedics
2900 metabolic measurement cart (Yorba Linda, CA).
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 Max and once steady
state had been achieved at each of the submaximal work rates during
Submax/Max. Further details concerning BP and exercise tests
methodology can be obtained from recent publications (32,
38).
Endurance exercise training program.
Participants trained under supervision and were required to complete 60 training sessions within 20 wk. Only subjects who completed at least 57 sessions (>95% of target) were defined as compliers and used for
investigating the training response. 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's O2 max for 30 min per
session. This was gradually increased to 50 min by the end of
week 14 at a 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
(32, 38).
Genotype determinations.
DNA was extracted from lymphoblastoid cell lines after a standard
protocol of digestion by proteinase K and purification with phenol-chloroform. PCR amplification targeted a region
[1,874-2,175 base pairs (bp)] in exon 1 covering codon 10, which
includes the polymorphic site at bp 2,005 [T C (leucine
proline)]. The primers were as follows:
5'-TTC-TCC-CTG-AGG-ACC-TCA-GTC-TTC-3' (sense) and
5'-TGG-GTT-TCC-ACC-ATT-AGC-ACG-3' (antisense). A PCR product of
283 bp was generated. The total volume of the PCR was 25 µl of a
reaction mixture containing 10 mM Tris · HCl (pH 8.3), 50 mM
KCl, 1.5 mM MgCl2, 0.001% gelatin, 200 µM of each dATP, dCTP, dGTP, and dTTP, 0.3 µM of each forward and backward primers, 0.75 unit of Taq polymerase (Perkin Elmer Cetus, Norwalk,
CT), and 10 ng of DNA. The amplification protocol was 1) one
cycle of denaturation at 95°C for 5 min; 2) 30 cycles of
denaturation at 95°C for 30 s, annealing at 60°C for 30 s, and extension at 72°C for 45 s; and 3) one final
5-min elongation cycle at 72°C. Preventive contamination measures
were taken by the inclusion of PCR reaction mixture without DNA
(negative control) in every run of amplification.
X174 DNA, digested with
HaeIII, was used as a length marker to estimate the size of
the digested DNA fragments. The allele without the mutation (145 bp)
was designated as leucine-10, whereas the allele with the point
variation (T C; leucine proline; 133 bp) site was designated as
proline-10.
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 phenotypes and genotypes were analyzed using a MIXED procedure in the SAS software package (SAS Institute, Cary, NC) for personal computer (version 6.12) (30). Nonindependence among family
members was adjusted for using a "sandwich estimator," which
asymptotically yields the same parameter estimates as ordinary
least-squares or regression methods, but the standard errors and
consequently hypothesis tests are adjusted for the dependencies. The
method is general, assuming the same degree of dependency among all
members within a family. Possible race-by-genotype interaction effects were tested by introducing an interaction term in the MIXED model in
addition to the genotype and race main effects. If the interaction term
was significant, association analyses were performed separately by
race. Baseline phenotypes were adjusted for the effects of age, gender,
and body mass index (BMI), whereas posttraining values were adjusted
for age, gender, and posttraining BMI. BP (BP = pretraining
BP 
posttraining BP) was adjusted for age, gender, baseline BMI,
and baseline value of the phenotype. All phenotypes were regressed on
up to a third-degree polynomial in age. In addition to the fully
adjusted models, analyses were also performed by adjusting for each
covariate 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 model
are reported.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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2 Tests revealed that, in both races, the allele
and genotype frequencies were not significantly (P > 0.05) different between men and women. Genotypic distributions for
blacks and whites were in agreement (P > 0.05) with
those expected under Hardy-Weinberg equilibrium (Table
2). The allele with the point variation
(proline-10) was less frequent. Because no significant genotype-gender
interaction effect was detected (not shown) for the variables under
study and given that there were similar allelic and genotypic frequency distributions in men and women, the data for both genders were pooled
for subsequent analysis. Because significant (P < 0.05) race-genotype interactions were found for sedentary-state SBP at
rest and 80% O2 max (Table
3) and at 100%
O2 max in the trained state (Table
4), analyses were performed within each
race.
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Among whites, the TGF-1 genotypes were significantly
(P < 0.05) associated with sedentary-state SBP at rest
as well as at exercise intensities of 50 W and 60 and 100%
O2 max (Table 3). At all these
intensities, leucine-10 homozygotes had significantly (P < 0.05) lower SBP than proline-10 homozygotes. In
contrast, among blacks, no genotypic effect on sedentary-state SBP was
evident (Table 3). Significant associations between the
TGF-1 genotypes and sedentary-state DBP were observed
only among whites at rest (Table 3).
In the trained state (Table 4), TGF-1 genotypes were
significantly (P < 0.05) associated with SBP at
rest and 80 and 100% O2 max
among whites. Leucine-10 homozygotes had significantly lower SBP
than both proline-10 homozygotes and leucine-10/proline-10 heterozygotes. However, among blacks, there was again no evidence of
association between the genotypes and trained-state SBP at rest or at
any exercise intensity (Table 4). Furthermore, in both races, no
association between genotype and DBP was observed in the trained state
(Table 4). Finally, neither SBP (Table 5) nor DBP was significantly
associated with the TGF-1 genotypes.
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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
phenotypes has been acknowledged for some time (3, 28, 35). However, information on the molecular and genetic basis of
these racial differences and how they relate to exercise and exercise
training has been lacking. The most important finding of this study was
the significant TGF-1 gene-race interaction for SBP at
rest and during exercise. The interaction reported in this study and
that recently reported by our laboratory (28) for the
angiogenin gene are among the first to provide evidence that the
genetic component of racial differences in BP acute response to
exercise in the sedentary and trained states can be defined in terms of
genes and DNA sequence variation.
Another relevant finding of the present study was the significant
association between the TGF-1 genotypes and SBP measured at rest and at moderate as well as maximal exercise intensities among
whites in the sedentary and trained states. It is noteworthy that
whites' homozygotes for the common leucine-10 allele had significantly
lower SBP than proline-10 homozygotes at rest and at exercise
intensities of 50 W and 60 and 100%
O2 max. These results suggest that
either the TGF-1 gene polymorphism in codon 10 per se or
a nearby polymorphism in the same gene or in another gene in linkage
disequilibrium with it plays a role in the SBP acute response to
submaximal and maximal exercise in sedentary and endurance-trained
whites. Although significant associations between genotype and the SBP
acute response to exercise were present in whites before and after
training, the TGF-1 gene marker does not seem to
contribute to individual differences in BP responses to endurance
training because there were no significant interactions or genotypic
effects on SBP or DBP in either race.
Different from the associations found among whites, in the present
study, TGF-1 genotypes were not associated with SBP of blacks. A previous study of this polymorphism (33)
reported that significant differences in allele and genotype
frequencies existed between black and white subjects for the codon-10
polymorphism. Nonetheless, that study only used 44 black subjects, and
the authors recognized that a larger study was necessary to establish
whether racial differences in TGF-1 allele and genotype
frequencies do exist. In contrast, the present study used a 75% larger
sample (76 unrelated black subjects) and found no differences in the allele and genotype frequencies between races. The similarity in
genotype frequency between races supports the notion of a true race-TGF-1 genotype interaction.
The novelty of our results highlights the importance of the choice of
marker. Previous studies have reported significant associations between
resting SBP and TGF-1 markers in the 5' region
(9) and codon 25 (9, 21) in whites (9,
21) as well as in blacks (21). In whites, the
TGF-1 5' region (+72) codon-10 and -25 markers are known
to be in strong linkage disequilibrium (P < 0.001)
(9). However, among the three markers, codon 10 is the most informative with a heterozygosity index of 0.49, whereas the other
two are 0.15 or less.
It is known that increased vascular shear stress, which occurs during
exercise, provokes the transcription and synthesis of endothelial
TGF-1 (25). It has been postulated that
TGF-1 could influence BP regulation by affecting NO,
ET-1 and/or renin secretion, which may then modify the physiology of
endothelial and vascular smooth muscle cells (10, 21, 22,
31). Early studies indicated that TGF-1 increased
mRNA levels and secretion of ET-1 in a medium of vascular endothelial
cells in vitro (18, 19). ET-1 is a potent vasoconstrictor
produced by vascular endothelium (18, 19) and vascular
smooth muscle cells (16). Its circulating levels have been
shown to be related to hypertension and vascular remodeling
(31). Another potential role of TGF-1 in
modulating vascular tone and reactivity is through the inhibition of
NO, a strong vasodilator (26). In addition,
TGF-1 can affect vascular remodeling by influencing
vascular smooth muscle cell growth (1) and by increasing
the production of ECM proteins (2, 24). All of the above
could link TGF-1 to reductions in vascular luminal diameter and distensibility and thus to an increase in peripheral vascular resistance (26), which could potentially explain
the TGF-1 genotypic effects on SBP during exercise
reported herein.
In conclusion, the present study provides support for the hypothesis of
an association between a TGF-1 marker in codon 10 and
SBP in response to acute exercise of moderate and maximal intensities
in the sedentary and trained states in whites but not in blacks. The
present findings support the notion that differences in resting and
exercise BP are partially mediated by genetic mechanisms.
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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 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. The work of M. Echegaray is supported by the Department of Biology of the University of Puerto Rico at Cayey. We also recognize the partial support provided by the School of Health Related Professions, University of Puerto Rico Medical Sciences Campus.
Address for reprint requests and other correspondence: M. A. Rivera, Dept. of Physical Medicine, Rehabilitation and Sports Medicine, Main Bldg. Office A-204, Univ. of Puerto Rico School of Medicine, 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 5 December 2000; accepted in final form 12 June 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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