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1 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808-4124; 2 Physical Activity Sciences Laboratory, Laval University, Québec, Canada G1K 7P4; 3 Division of Biostatistics and 7 Departments of Genetics and Psychiatry, Washington University Medical School, St. Louis, Missouri 63110; 4 School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, Minnesota 55455; 5 Department of Kinesiology, Indiana University, Bloomington, Indiana 47405; and 6 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
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study aimed to identify human genomic regions that
are linked to maximal oxygen uptake
(
O2 max) in
sedentary individuals or to the responsiveness of
O2 max to a
standardized endurance training program. The results of a genomic scan
based on 289 polymorphic markers covering all 22 pairs of autosomes
performed on the Caucasian families of the HERITAGE Family Study are
presented. The mean spacing of the markers was 11 cM, and a total of 99 families and 415 pairs of siblings were available for the study.
O2 max in the
sedentary state was adjusted for the effects of age, sex, body mass,
fat mass, and fat-free mass, whereas the
O2 max
response was adjusted for age and baseline level of the phenotype. Two analytic strategies were used: a single-point linkage procedure using
all available pairs of siblings (SIBPAL) and a multipoint variance components approach using all the family data (SEGPATH). Results indicate that linkages at P values of 0.01 and better are observed with markers on 4q, 8q, 11p, and 14q for
O2 max before
training and with markers on 1p, 2p, 4q, 6p, and 11p for the change in
O2 max in
response to a 20-wk standardized endurance training program. These
chromosomal regions harbor many genes that may qualify as candidate
genes for these quantitative traits. They should be investigated in
this and other cohorts.
genetic markers; quantitative trait locus; linkage; candidate genes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MAXIMAL OXYGEN uptake
(O2 max) varies
considerably among sedentary adults. In a recent report (3), we have
shown that there is significant familial aggregation for
O2 max in the sedentary state even when the data are adjusted for age, sex, body
mass, and body composition. These observations were derived from the
HERITAGE Family Study, and they indicate that the heritability of
O2 max among
sedentary adults after adjustment for the above covariates could be as
high as 50% of the total phenotypic variance, although this value is
undoubtedly inflated by nongenetic familial factors.
Twin and other family studies have been published in the peer-reviewed
literature on this topic over the past three decades (6, 12,
17-21, 23, 31). Despite the fact that these studies vary
considerably in sample size, phenotype measurements, data adjustment
procedures, and analytic strategies, they generally concluded that
there is a significant genetic component to
O2 max in the
untrained state.
Moreover, there is evidence that the trainability of
O2 max is
characterized by a significant level of familial aggregation. For
instance, members of the same pairs of identical twins are significantly more alike than unrelated individuals in the
O2 max increase
following exposure to a standardized training program. This was
confirmed by the results of three different experimental studies with
identical twins (16, 26, 29). The findings of these studies are
remarkably concordant: the intraclass correlations for the intrapair
resemblance in the
O2 max
changes with training range from 0.65 to 0.77. The F ratios of
the between-pair variance in
O2 max gain to the
within-pair variance are quite similar, with a range from 6 to 9 (4).
Such results have been further supported by the findings from the
HERITAGE Family Study (1). The
O2 max response to the
standardized training regimen of the HERITAGE Family Study exhibited
familial aggregation, with some families characterized by a
high-trainability pattern and others by low responsiveness. The maximal
heritability of O2 max trainability among the HERITAGE families of Caucasians reached 47%
(1).
Ultimately, the nature of the genetic effects on human variation in
O2 max in the untrained
state and in response to training will have to be resolved at the gene
and molecular level. A handful of studies have considered the role of a
few candidate genes on O2 max in sedentary
adults or O2 max
responsiveness to training (7) with mixed results. Another approach is
to focus on the detection of quantitative trait loci (QTL) affecting
these phenotypes. In a preliminary paper based on this strategy, we
have reported the results of a first screen of chromosome 22 using
seven polymorphic markers (13). No evidence for a QTL affecting
O2 max in the sedentary
state or the changes in
O2 max with training
was uncovered.
Here, we report the results of a genomic scan, based on 289 markers
covering all autosomes, performed on the Caucasian families of the
HERITAGE Family Study with a view to identify the genomic regions
encoding genes contributing to human heterogeneity in O2 max in the untrained
state and its trainability.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Sample
The HERITAGE Family Study was designed to investigate the role of the genotype in cardiovascular, metabolic, and hormonal responses to aerobic exercise training and the contribution of regular exercise to changes in selected cardiovascular disease and diabetes risk factors. Five centers located at Indiana University, Pennington Biomedical Research Center, University of Minnesota, Texas A&M University, and Washington University are presently involved in the HERITAGE Family Study consortium. The study design, sample, and protocol have been described earlier (5).A total of 481 individuals from 99 two-generation families of Caucasian
descent (236 men, 245 women) were available for this study. The
following criteria were applied to screen subjects for participation.
First, individuals were required to be between the ages of 17 and 65 yr
(17-40 yr of age for offspring and 
65 yr of age for parents).
Second, all participants were required to be sedentary at baseline.
Third, individuals with a body mass index >40 kg/m2 were
excluded unless they were able to meet the demands of the exercise
tests and exercise training program. Fourth, resting blood pressure
levels could not exceed 159 mmHg for systolic and 99 mmHg for
diastolic. Antihypertensive drug therapy was also a cause for
exclusion. Participants were required to be in good physical health and
able to complete the 20-wk exercise program. Further details about the
study, including inclusion and exclusion criteria, can be found in
Bouchard et al. (5). Informed written consent was obtained from all
subjects. The study was approved by the Institutional Review Board of
each participating institution.
Exercise Training Program
The training program was conducted on cycle ergometers (Universal Aerobicycle, Cedar Rapids, IA) interfaced with a Mednet computer system (Universal Gym Mednet, Cedar Rapids, IA) to control the power output of the ergometers so that constant training heart rates could be maintained. Subjects started training at a heart rate associated with 55% of the initialO2 max for 30 min/day and gradually progressed to 75% of the heart rate of the initial O2 max for 50 min/day
at the end of 14 wk. They maintained this intensity and duration
throughout the remaining 6 wk. Frequency was maintained at three
sessions per week throughout the 20-wk training program. The power
output of the cycle ergometer was adjusted automatically to the heart
rate response of the subject at all times during all training sessions.
All training sessions were supervised on site. A detailed description
of the training program can be found elsewhere (5, 30).
Maximal Oxygen Uptake Measurements
Each individual was examined with a battery of measurements before and after the 20-wk standardized exercise program. Two maximal exercise tests designed to lead toO2 max on a
cycle ergometer were performed on 2 separate days at baseline and again on 2 separate days after training on a SensorMedics 800S (Yorba Linda,
CA) cycle ergometer connected to a SensorMedics 2900 metabolic measurement cart. The tests were conducted at about the same time of
day, with at least 48 h between the two tests. An electrocardiogram was
used to monitor heart rate. Gas exchange variables
[O2 consumption (O2), CO2
production (CO2), minute
ventilation, and respiratory exchange ratio (RER)] were recorded
as a rolling average of three 20-s intervals. The criteria for
O2 max were
RER >1.1, plateau in O2
(change of <100 ml/min in the last three 20-s intervals), and a heart
rate within 10 beats/min of the maximal heart rate predicted for that
age. All subjects achieved a
O2 max by at least
one of these criteria in at least one of the two tests, both pre- and
posttraining. In the first test, subjects exercised at a power output
of 50 W for 3 min, followed by increases of 25 W each every 2 min until
volitional exhaustion. For older, smaller, or less fit individuals, who
were generally the older mothers among the family members, the test was
started at 40 W, with increases of 10-20 W each every 2 min
thereafter. In the second test, subjects exercised for ~10 min at an
absolute (50 W) and then for ~10 min at a relative power output
equivalent to 60%
O2 max. They then
exercised for 3 min at a relative power output that was 80% of their
O2 max, after which
resistance was increased to the highest power output attained in the
first maximal test. If subjects were able to pedal after 2 min, power output was increased every 2 min thereafter until they reached volitional fatigue.
If both values were within 5% of each other, the average
O2 max from
these two tests was taken as the
O2 max for that subject and used in this analysis. If they differed by more than 5%, the higher
O2 max value was
used. The reproducibility of O2 max in these
subjects was examined and was characterized by an intraclass
correlation coefficient of 0.97 for repeated tests with a coefficient
of variation of 5% and no difference among clinical centers (3, 30).
The O2 max response
was defined as the difference (ml O2/min) between
posttraining O2 max and baseline O2 max
(i.e., O2 max
response = posttraining O2 max minus baseline
O2 max).
Molecular Studies
Genomic DNA was prepared from permanent lymphoblastoid cells by the proteinase K and phenol/chloroform technique. DNA was dialyzed four times against 10 mM Tris-1 mM EDTA (pH 8.0) buffer for 6 h at 4°C, and ethanol was precipitated.Choice of markers. Microsatellite markers (di-, tri-, and tetranucleotide repeat) were selected from different sources but mainly from the Marshfield panel version 8a (http://www.marshmed.org/genetics) and the Location Database (LDB) maps (January 1999 version) from Southampton, UK (http://cedar.genetics.soton.ac.uk). The LDB summary map was also used to look for candidate genes 10 cM on each side of the markers yielding the strongest results. The mean spacing for the 289 markers was 11 cM with a range from 0.2 to 51 cM.
PCR conditions. PCR conditions and genotyping have been described in detail elsewhere (9). Briefly, PCR reactions were conducted using 250 ng of genomic DNA, 0.1 pmol of the forward primer coupled to the infrared tag IRD800 or IRD700 (LICOR), and 0.4 pmol of the reverse untagged primer (Research Genetics), 125 µM dNTPs, and 0.3 units Taq polymerase (Perkin-Elmer or Pharmacia) in PCR buffer (100 mM Tris · HCl, pH 8.3, 15 mM MgCl2, 0.5 M KCl, and 0.01% gelatin) for a final volume of 10 µl. PCR cycles followed a two-step procedure: 1 cycle at 93°C for 5 min, 10 cycles at 93°C for 20 s and 57°C for 60 s, and 24 cycles at 93°C for 20 s and 52°C for 60 s. Annealing temperature was defined according to the melting temperature of the primers used and ranged between 52 and 67°C, with a difference of 5°C being maintained between the two annealing temperatures.
Marker analysis. Automatic infrared DNA sequencers from LICOR were used to detect the PCR products. One microliter of each of the 52 samples, including up to five different markers, spaced with standards at each of the four samples, was applied to the gel. Standards were produced by PCR from a PUC19 plasmid using a tagged M13 forward primer (LICOR) and corresponding untagged reverse primer for each standard. The 18-cm long gel was run for 1.5-2 h. At the end of the run, an electronic image of the gel was produced and used for genotyping.
Genotyping. Automatic genotyping was performed using the computer software SAGA (Rick McIndoe, Roger Bumgarner, and Russ Welti, University of Washington, Seattle, WA; LICOR). In this process, sample and standard lanes were automatically found, the different markers were located on the gel, bands for each sample were identified, and genotyping was done simultaneously for a given marker on all the subjects of the study. After a manual edition of the typing, results were exported directly to a local dBase IV database (GENEMARK) in which a procedure had been developed to check for misinheritance (incompatibilities among the genotypes) within nuclear families and extended pedigrees. Subjects with incompatibilities were excluded from the database by GENEMARK and retyped completely for the incompatible markers, i.e., from the PCR reaction to the genotyping. Less than 5% of the subjects had to be retyped (mainly because of insufficient DNA amplification).
Data Adjustment
TwoO2 max phenotypes
are considered.
O2 max at baseline
was analyzed after adjustment for the effects of age (up to a cubic
polynomial), sex, body mass, fat mass, and fat-free mass using stepwise
multiple regression procedures, separately in each of the four
sex-by-generation groups, and retaining only those terms that were
significant at the 5% level. Fat mass and fat-free mass were estimated
from an underwater weighing assessment of body density as recently
described (33). The resulting squared residuals were similarly
regressed on another polynomial in age (to adjust for
heterocedacticity). The phenotype used in the genetic analysis was thus
adjusted for relevant covariate effects in both the mean and variance.
The phenotype was standardized to a mean of zero and a standard
deviation of one. The percentage of variance accounted for by these
covariates was quite large, ranging from 42.2% to 57.6%.
The response of
O2 max to training
was adjusted for age and baseline
O2 max using a
stepwise multiple regression procedure. Briefly, the response variable
was regressed on up to a cubic polynomial in age plus baseline value
within four sex-by-generation groups (fathers, mothers, sons, and
daughters). Only terms significant at the 5% level were retained. The
resulting squared residuals were similarly adjusted for effects on the
variance; the final adjusted phenotype was standardized to a mean of
zero and a standard deviation of one. Significant terms (percentage of
variance) in each of the sex-by-generation groups for the
O2 max response phenotype were seen only in sons (9.2%) and daughters (5.0%). SAS
(version 6.08) for PC was used for the regression analysis.
Statistical Analysis
First, single-point linkage analysis using all available sibling pairs was performed on these two phenotypes (SIBPAL; SAGE version 3.0). Second, analyses were carried out using the multipoint variance components analytic strategy implemented in SEGPATH (25). This is an extension of a path model for analysis of family resemblance (24) in which correlations among family members are modeled as functions of the allele sharing at a marker locus and a residual component including genetic as well as shared environmental effects. In addition to the trait locus heritability (h2g) and the residual heritability (h2r), the spouse correlation and excess sibling resemblance beyond that predicted under the genetic model were estimated by maximum likelihood. Linkage was tested by the likelihood ratio test of the null hypothesis h2g = 0. Multipoint estimation of identical by descent was used in the SEGPATH analysis, whereas a single-point approach was implemented in SIBPAL. The number of families available for the SEGPATH analysis was 99. The SIBPAL linkage analyses were undertaken with 415 pairs of siblings at baseline and 327 for the response to training. Suggestive evidence of linkage was defined as P < 0.01, whereas weaker but potentially useful evidence of linkage was identified as 0.01 < P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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General trends in the linkage results are depicted in Figs.
1 and 2 for the
22 autosomes. In Fig. 1, the evidence for linkage (P values)
from SEGPATH and SIBPAL is illustrated for the baseline O2 max (adjusted for
age, body weight, fat mass, and fat-free mass within each sex).
Suggestive evidence of linkage can be seen for chromosomes 4, 8, 11, and 14 (P < 0.01). The training response (adjusted for
age and baseline level by sex) results are shown in Fig. 2. Again,
suggestive evidence of linkage is observed for chromosomes 1, 2, 4, 6, and 11.
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The details of all suggestive linkages for the pretraining
O2 max are summarized
in Table 1. The region with the highest significance level with SEGPATH is located on the long arm of chromosome 4 (4q12) at map position 61.658 cM. Three additional regions
for baseline O2 max
were identified with SIBPAL. These regions are located on chromosome
14q21.3 at map position 49.255 cM, chromosome 8q24.12 (128.157 cM), and
chromosome 11p15.1 (21.174cM). Moreover, 11 regions on seven
chromosomes (chromosomes 1, 3, 4, 7, 8, 11, 13) with SEGPATH and 10 markers on six chromosomes (chromosomes 1, 2, 3, 4, 7, 22) with SIBPAL
showed weaker but possibly useful evidence of linkage (0.01 < P < 0.05) with
O2 max in the sedentary state (Table 2).
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Multipoint analyses (SEGPATH) revealed two regions and single-point
analyses (SIBPAL) revealed three regions with suggestive evidence of
linkage with the O2 max
training response. The multipoint signals are located on chromosomes 4 (4q26, 127.793 cM) and 6 (6p21.33, 28.788 cM), whereas the single-point
linkages are seen with markers on chromosomes 11 (11p14.1, 31.272 cM),
1 (1p11.2, 125.032 cM), and 2 (2p16.1, 62.602 cM). In addition, weaker
but potentially useful linkages (0.01 < P < 0.05) were
found with SEGPATH for regions located on chromosomes 3, 6, 9, and 13 plus for 15 markers on chromosomes 1, 3, 5, 6, 7, 11, 13, 15, 19, and 21 with SIBPAL (Table 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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From the quantitative genetic evidence gathered in twin and family
studies, it is justified to search for QTLs and, eventually, genes and
mutations pertaining to
O2 max in the sedentary
state and its responsiveness to training. The genetic dissection of these two phenotypes and their determinants will require a wide array
of designs and technologies. At this time, only one linkage study has
been reported in humans, but it has dealt with a limited number of
markers on one chromosome only (13). Other studies have focused on
candidate genes encoded in the nuclear DNA and on a few mitochondrial
DNA sequences.
In the same population, we have earlier reported a maximal heritability
of ~50% for the baseline
O2 max data (3). On the
other hand, the maximal heritability estimate of the
O2 max response to
training reached 47% for the same sample of families with 2.5 times
more variance between families than within families. Thus the familial
factors underlying
O2 max in sedentary
families are quantitatively similar to those underlying its response to exercise training. However, although they are quantitatively about the
same, the familial and genetic factors underlying the two phenotypes
appear to be different, as indicated by the noncomparability of the
linkage results for baseline
O2 max and
O2 max response. From
the earlier observations on identical twins and nuclear families plus
the recent data on the HERITAGE Family Study cohort, we previously concluded that O2 max
in the sedentary state and its trainability are highly familial with a
significant genetic component (1, 3). It should therefore be possible
to identify the genes and mutations responsible for the variability in
both phenotypes. However, it must be recognized at the outset that it
is unlikely that a single gene or very few loci will be sufficient to
define the genetic component of
O2 max and trainability.
A few reports on the topic of genetic markers and performance have appeared over the past 30 years or so. The study of elite performance by means of genetic markers was first conducted during the 1968 Olympic Games in Mexico City (11). The purpose of that study was to test if there was any association between participation in the Olympic Games as an athlete and allelic variation in single-gene blood systems. Results indicated that participation in the 1968 Olympic Games was not associated with allelic variations in red blood cell antigens or enzyme variants of red blood cells. A second effort was carried out during the 1976 Olympic Games in Montreal (8, 10). No significant differences between Caucasian elite endurance athletes and controls were observed for genetic markers in red blood cell antigens and four red blood cell enzymes.
Since then, a handful of papers have dealt with the potential
contribution of a few candidate genes. For instance, three studies have
reported an association between the insertion allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D)
polymorphism and indicators of performance (14, 15, 22). The
ACE locus is encoded on 17q23. In the present study, no
evidence of linkage was observed on chromosome 17 for either baseline
O2 max or its
responsiveness to training. Therefore, it is not yet clear whether the
ACE I/D polymorphism is truly of importance for physical performance in general or endurance performance in particular.
Skeletal muscle-specific creatine kinase (CKMM) is a
legitimate candidate gene (19q13.22) to investigate in relation to
endurance performance. Because CKMM activity level is two
times greater in type II (fast-twitch) than in type I fibers (34), a
low CKMM activity level is typical of the skeletal muscle of
endurance athletes. An early study indicated that a CKMM
protein charge variant was weakly associated with the ability to
perform a 90-min endurance test (2). In addition, research on
transgenic mice indicates that a low CKMM activity is
associated with improved skeletal muscle resistance to fatigue (32).
More recently, a sibling pair linkage study has shown a weak genetic
linkage between the CKMM locus and changes in
O2 max (age,
sex, and pretraining O2 max adjusted) in the
HERITAGE Family Study (28). This linkage was suggested again in the
present study with a P value of 0.026 (Table 3). Moreover, we
have reported a significant association between the CKMM
genotype and the
O2 max
response to 20 wk of endurance training in both parents and adult
offspring of the HERITAGE Family Study (27). One-third of all
homozygotes for the less-frequent allele (CKMM Nco I
polymorphism in the 3' untranslated region) were observed in the
low-responder group (lowest decile of response), whereas this genotype
was not seen in any high responders (upper decile of response). The
CKMM genotype accounted for ~10% of the variance of
O2 max response.
The chromosomal regions showing suggestive linkages with
O2 max in the sedentary
state or in response to endurance training in the present paper encode
several potential candidate genes. The marker D4S3248 on chromosome 4, which was the strongest signal with the baseline
O2 max in multipoint
analyses, is located close (0.2 cM) to the 
-sarcoglycan gene.
-Sarcoglycan is part of the dystrophin-glycoprotein complex, which
acts as a structural link between the cytoskeleton of muscle and the
extracellular matrix. It is thought to confer stability to the
sarcolemma and protect muscle cells from contraction-induced damage. A
gene of another dystrophin-associated protein, syntrophin -1,
located 5.9 cM from the D8S592 marker, showed suggestive single-point linkage evidence with the baseline
O2 max. In addition,
the genes encoding 
-sarcoglycan (13q12.11), dystrophin-associated glycoprotein 1 (3p21.31), and lamin A/C (1q21.2) are located within 2.3 to 6.2 cM from markers, showing weak but potentially useful linkages
with O2 max in the
sedentary state. The marker (D14S587) showing the strongest evidence of
linkage with the baseline
O2 max in SIBPAL is
located in the vicinity of the liver glycogen phosphorylase (0.6 cM)
and the GTP cyclohydrolase I (1.8 cM) genes. GTP cyclohydrolase I is a
rate-limiting enzyme in the synthesis of tetrahydrobiopterin, an
essential cofactor of nitric oxide synthase.
A restriction fragment length polymorphism marker on chromosome 11p15.1
within the sulfonylurea receptor (SUR) gene exhibited one of
the most significant linkages with
O2 max in the sedentary state. SUR is expressed in pancreatic -cells where it
forms ATP-sensitive potassium channels together with an inward
rectifier potassium channel member, Kir6.2, and is thereby involved in
the regulation of insulin secretion. One cannot conclude from this
linkage result that SUR itself has any effect on
O2 max variability. An
alternative explanation could be that the SUR marker is a
surrogate for a relationship with another gene such as Kir6.2
(KCNJ11), which is located close to the SUR
locus. Unlike SUR, Kir6.2 is expressed in several tissues,
including heart and skeletal muscle, where it plays a role in the
coupling of cell metabolism to membrane potential.
Potential candidate genes located close to markers with suggestive
linkages to O2 max
training response include the voltage-gated potassium channel gene
(KCNA4) on chromosome 11p14.1 (0.1 cM from the marker), the
pancreatic colipase (CLPS, 0.8 cM) gene and the hemochromatosis locus (HFE, 1.3 cM) on chromosome 6p21.33,
the fatty-acid binding protein 2 (FABP2, 0 cM) gene and the
long QT syndrome 4 locus (LQT4, 4.0 cM) on chromosome 4q26,
the calmodulin 2 (CALM2, 0.5 cM) and the calcineurin B
(PPP3R1, 3.4 cM) genes on chromosome 2p16.1, and the
3--hydroxysteroid dehydrogenase (HSD3B1, 0.1 cM) and the
cardiac muscle calsequestrin (CASQ2, 5.5 cM) genes on
chromosome 1p11.2. These genes are involved in cardiac contractility
(KCNA4, LQT4), long-chain fatty acid absorption (CLPS, FABP2), calcium homeostasis and signaling
in skeletal and cardiac muscle (CALM2, PPP3R1,
CASQ2), and steroid hormone synthesis (HSD3B1).
Although there is no direct evidence to support the notion that they
are involved in human trainability, one could hypothesize that they
contribute to interindividual variation in training response.
There was not a high degree of concordance between the single point and multipoint linkage results in the present study. The differences in the findings are likely explained by the relatively small sample sizes available for such studies, the marker spacing, which is relatively large in some chromosomal areas, and perhaps misspecification of the location of markers on the genetic map. The latter two factors could have had influences on the multipoint linkage results, particularly if errors of location exist in the current map, but would not have affected the single-point findings. Moreover, it should be recognized that, even though a panel of 289 markers is reasonably large for a first genomic screen, a more dense and accurate map will likely yield more and perhaps stronger signals in the future.
In summary, multipoint and single point linkage studies performed on
the Caucasian families of the HERITAGE Family Study have revealed some
indications of linkages with
O2 max in the sedentary state and with its responsiveness to training. None of the linkages is
very strong. However, several linkages were found at the 0.01 level and
better with markers on 4q, 8q, 11p, and 14q for
O2 max before training
and with markers on 1p, 2p, 4q, 6p, and 11p for the gain in
O2 max in response to
20 wk of a standardized endurance training program. These chromosomal
regions encode several candidate genes that should be investigated further.
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ACKNOWLEDGEMENTS |
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Thanks are expressed to all the coprincipal investigators, investigators, coinvestigators, local project coordinators, research assistants, laboratory technicians, and secretaries who have contributed to the study and to Diane Drolet, MSc, for assistance with the preparation of this manuscript.
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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-45670 (C. Bouchard, principal investigator), HL-47323 (A. S. Leon, principal investigator), HL-47317 (D. C. Rao, principal investigator), HL-47327 (J. S. Skinner, principal investigator), and HL-47321 (J. H. Wilmore, principal investigator). A. S. Leon is partially supported by the Henry L. Taylor Professorship in Exercise Science and Health Enchancement.
* Original submission in response to a special call for papers on "Molecular and Cellular Basis of Exercise Adaptations."
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, Louisiana State Univ., 6400 Perkins Rd., Baton Rouge, LA 70808-4124 (E-mail: bouchac{at}pbrc.edu).
Received 31 August 1999; accepted in final form 29 October 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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