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Physiol. Genomics 15: 20-26, 2003. First published July 15, 2003; doi:10.1152/physiolgenomics.00061.2003
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Received 9 April 2003; accepted in final form 7 July 2003.
Physiological Genomics 15:20-26 (2003)
1094-8341/03 $5.00 © 2003 American Physiological Society

Sequence variation in hypoxia-inducible factor 1{alpha} (HIF1A): association with maximal oxygen consumption

Steven J. Prior1, James M. Hagberg1, Dana A. Phares1, Michael D. Brown1, Liane Fairfull2, Robert E. Ferrell2 and Stephen M. Roth1,2

1 Department of Kinesiology, University of Maryland, College Park, Maryland 20742
2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 References
 
Hypoxia-inducible factor 1 (HIF1) is a DNA transcription factor composed of two subunits, one of which is regulated by hypoxia (HIF1{alpha}, encoded by HIF1A). Genes regulated by HIF1 are involved in the processes of angiogenesis, erythropoiesis, and metabolism, making HIF1A a candidate gene in establishing maximal oxygen consumption (V·O2 max) before and after aerobic exercise training. The purpose of the present study was to screen HIF1A for sequence variation and determine whether such variation is associated with V·O2 max before and after aerobic exercise training. A total of 233 Caucasian and African-American subjects were available for screening of HIF1A and determination of allele frequencies, with 155 of those subjects used to study V·O2 max in relation to identified variants. We measured V·O2 max before and after 24 wk of aerobic exercise training. Screening revealed several rare and common polymorphisms in HIF1A with race-specific allele frequencies. African Americans with AT or TT genotype at the A-2500T locus exhibited significantly lower baseline V·O2 max compared with those of AA genotype (21.9 ± 0.99 vs. 25.1 ± 1.0, P = 0.03). An age by P582S (C/T) genotype interaction was observed in Caucasian subjects, such that those of CT or TT genotype exhibited significantly lower change in V·O2 max after training than those of CC genotype when compared at ages 65 and 60 yr, but not at age 55 yr. No other significant differences were noted among genotype groups at the A-2500T, P582S, or T+140C sites. Based on these findings, we conclude that HIF1A sequence variation is associated with V·O2 max before and after aerobic exercise training in older humans.

exercise; sex; genetics; polymorphism; race


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 References
 
CARDIORESPIRATORY FITNESS, as measured by maximal oxygen consumption (V·O2 max), is inversely associated with cardiovascular and all-cause mortality and is responsive to aerobic exercise training. However, there is a high degree of variability in V·O2 max among individuals before, and in response to, an aerobic exercise training program (3). This variability persists among individuals of the same age, sex, and race (3). Although some proportion of this variability is certainly due to environmental factors (e.g., physical activity), evidence from several twin- and family-based heritability studies indicates that there is a significant contribution of genetics to the variability in V·O2 max. Recent studies have shown that the heritability estimate for V·O2 max may be as high as 59% (1, 6), and as high as 47% for the response of V·O2 max to exercise training, although nongenetic familial influences likely inflate these values (1). Previous studies have shown correlations of measured V·O2 max ranging from 0.71–0.95 in monozygotic twins compared with 0.36–0.51 in dizygotic twins (2, 13, 14).

Hypoxia-inducible factor 1 (HIF1) is a DNA transcription factor that acts to regulate the transcription of numerous genes in humans in response to hypoxic stimuli (11, 12, 18, 19). As a DNA transcription factor, HIF1 has the ability to bind hypoxia-response elements (HREs) embedded in the sequence of numerous human genes. Genes responsive to HIF1 are involved in the processes of erythropoiesis, angiogenesis, and metabolism and include those encoding erythropoietin (Epo), vascular endothelial growth factor (VEGF), and the VEGF receptor FLT-1 (Fms-like tyrosine kinase-1) (18, 19). Because of its ability to regulate transcription of these genes, HIF1 has been shown to play a role in the long-term homeostatic process in response to hypoxia (10).

The functional HIF1 protein is composed of two subunits, HIF1{alpha} and HIF1ß, with the HIF1{alpha} subunit being responsive to hypoxia. HIF1{alpha} protein levels are closely regulated by oxygen tension in human tissues. Under normoxic conditions, HIF1{alpha} is rapidly degraded, but during periods of intracellular hypoxia, levels of HIF1{alpha} protein rise as the rate of its proteosomal degradation falls (11, 21, 26). This posttranslational regulation of HIF1{alpha} appears to be the rate-limiting step in HIF1 complex formation. As HIF1{alpha} levels rise, there is increased binding of HIF1ß, resulting in an increased level of HIF1 in hypoxic tissues (26), with resulting influences on transcription of a number of downstream targets.

A hypoxic condition can occur in healthy humans through multiple mechanisms. Aerobic exercise creates an increased demand for oxygen resulting in a local hypoxia in working skeletal muscle tissue (16, 17). Even with the corresponding increase in supply of oxygen to skeletal muscle (through increased cardiac output, blood pressure, regional blood flow, etc.), the PO2 in working human skeletal muscle can reach levels as low as 2–3 Torr (15, 24). Considering that PO2 in resting human skeletal muscle is ~30 Torr, the entire physiological range of skeletal muscle PO2 falls within the range that Jiang et al. (11) describe as that where the most dramatic alterations in HIF1{alpha} expression occur, with the half-maximal response occurring at 10–15 Torr. As long as the aerobic exercise stimulus is present, this local hypoxic condition would be expected to persist in working skeletal muscle, resulting in increased levels of HIF1.

In addition to this posttranslational, hypoxia-mediated regulation, the function of HIF1{alpha} may also be influenced by genetic variation in HIF1A, the gene coding for HIF1{alpha}. As polymorphisms may influence the expression and/or structure of HIF1{alpha} mRNA or protein, the presence, function, and stability of HIF1{alpha} protein may be affected. Because of the broad actions of HIF1, and more specifically HIF1{alpha}, we hypothesized that variability in the gene encoding HIF1{alpha} would contribute to the variance in V·O2 max. Thus, the purpose of this study was to screen the DNA sequence of HIF1A to identify polymorphisms and determine whether associations exist between identified variants and V·O2 max, both before and after an aerobic exercise training program in older humans.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 References
 
Subjects
Screening of HIF1A sequence.
Subjects available for screening of HIF1A and genotyping for the determination of allele frequencies included 233 Caucasian (n = 142) and African-American (n = 91) men and women from throughout the United States of America. All subjects gave informed consent as approved by the Institutional Review Boards at the University of Maryland and the University of Pittsburgh.

Exercise intervention.
A total of 155 Caucasian (n = 126) and African-American (n = 29) subjects were available for aerobic exercise training and were used to study the potential relationship between baseline V·O2 max and HIF1A polymorphisms. Not all subjects completed the exercise intervention, so only the 123 subjects who completed the exercise intervention (101 Caucasian, 22 African-American) were included in the analyses of the change in V·O2 max and V·O2 max after exercise training. Subject selection for aerobic exercise training has been previously described (25), with all subjects screened as sedentary and in good health. All subjects gave informed consent as approved by the Institutional Review Boards at the University of Maryland and the University of Pittsburgh.

Sequencing/Screening
The 15 exons, corresponding exon/intron boundaries, and 2,624 base pairs (bp) of 5' flanking sequence of HIF1A were screened for variation in randomly selected subjects using standard DNA sequencing techniques. Amplimers of selected regions were sequenced directly using the BigDye Terminators reaction kit (Applied Biosystems) and analyzed on an ABI PRISM 3700 fluorescence sequencer (Applied Biosystems). Sequences were aligned for comparison using Sequencher v4.1 (Gene Codes). Genetic variation was verified by both bi-directional sequencing and restriction fragment length polymorphism (RFLP) analysis. As polymorphic loci were identified (Fig. 1), allelic frequencies were determined through genotype analysis in racially homogeneous groups.



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  		Fig. 1. Identified variants in the HIF1A sequence. Six rare variants (q < 0.05) are noted below the gene structure, while three common variants further investigated in relation to V·O2 max are noted above the gene structure. NOTE: Figure is not drawn to scale. UTR, untranslated region. Int, intron.

 
Genotyping
Polymorphisms were selected for genotyping based on allele frequency and available populations. Genomic DNA was extracted from peripheral lymphocytes using standard methods, and selected sites were genotyped. Table 1 summarizes the genotyped variants, the PCR primers, conditions, and genotyping method. The HIF1A A-2500T single nucleotide polymorphism (SNP) was genotyped using RFLP analysis (Ssp1 cuts T). The T+140C site in intron 14 was genotyped using fluorescence polarization (4). The P582S (C85T in exon 12) and A-1155X sites were genotyped by direct sequencing using standard methods.


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  		Table 1. PCR conditions for specific sites in HIF1A

 
Exercise Intervention
The Gene Exercise Research Study protocol has been described previously (25). Briefly, these subjects undergo 24 wk of standardized aerobic exercise training, beginning at a training volume of three sessions of 20 min at 50% V·O2 max per week. This volume is increased gradually to three sessions of 40 min at 70% V·O2 max per week, a level maintained for the final 14 wk of the intervention. All training is supervised by study personnel, and training intensity is monitored using wrist heart rate monitors. Throughout the intervention, subjects are encouraged to maintain their baseline body weight to account for the potential affects of weight loss on physiological outcomes.

Maximal Oxygen Consumption
Maximal oxygen consumption (V·O2 max) was assessed during a graded exercise test using a validated indirect calorimetry system consisting of a mixing chamber, bi-directional turbine, and mass spectrometer. Values of V·O2 max were averaged in 30-s increments. Subjects underwent a graded exercise test on a treadmill to maximal effort as determined by standard physiological criteria. The test consisted of a continuous sequence of 2-min stages where speed was fixed throughout the test, and grade was increased 2% in each stage. V·O2 max was defined as the highest oxygen consumption value obtained for a full 30-s increment.

Statistics
Chi-square analysis was used to determine deviations of genotype distribution from expected Hardy Weinberg equilibrium. Haplotype frequencies were estimated as previously described (22), and D' was calculated to estimate linkage disequilibrium between the P582S and T+140C sites in Caucasians and between the P582S, T+140C, and A-2500T sites in African Americans (5). General linear models, especially ANCOVA, were used to test for associations between specific HIF1A polymorphisms and baseline V·O2 max, change in V·O2 max in response to aerobic exercise training, and V·O2 max after exercise training. Covariates included age (in all analyses), sex (when men and women were analyzed together), baseline V·O2 max (when analyzing V·O2 max after training and change in V·O2 max with training), and body weight (when analyzing absolute V·O2 max). All values are expressed as means ± SE. Statistical significance was accepted at P <= 0.05. With the exception of the analysis of T+140C genotype and V·O2 max in African-American subjects, all analyses had the statistical power (ß > 0.80) to detect a 15% difference in V·O2 max between genotype groups.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 References
 
HIF1A Sequencing/Screening
Sequencing of HIF1A revealed several rare and common polymorphisms that have not been reported elsewhere to date. All variants are shown in Fig. 1, while common polymorphisms and observed allele frequencies are reported in Table 2. The A-2500T SNP was found only in African-American subjects [p(A) = 0.68, q(T) = 0.32] and is predicted to alter the binding site of the transcription factor CdxA. A missense polymorphism, P582S, was observed in exon 12 (C/T at bp 85). The rare T-allele is predicted to result in a proline-to-serine change in the amino acid sequence of the protein. The T-allele was found in both Caucasian and African-American subjects with observed frequencies being p(C) = 0.88, q(T) = 0.12 and p(C) = 0.97, q(T) = 0.03, respectively. One variant was noted in intron 14, 140 bp downstream of exon 14 (T+140C). The polymorphism was found in both African-American and Caucasian subjects with allele frequencies being p(T) = 0.29, q(C) = 0.71 and p(T) = 0.77, q(C) = 0.23, respectively. Analyses for all common variants within race groups revealed that no genotype frequencies deviated from expected Hardy-Weinberg equilibrium (P = 0.08–0.98). With the exception of the A-1155X insertion/deletion polymorphism, genotyping was not pursued for the rare variants (all with q < 0.05). The A-1155X variant was observed in only 1 of 222 screened chromosomes [p(A) = 0.995, q(X) = 0.005].


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  		Table 2. Allele frequencies for common variants within HIF1A

 
Neither complete, nor strong evidence of linkage disequilibrium was observed among any alleles in either Caucasians or African Americans. Within Caucasian subjects we estimated linkage disequilibrium between the P582S and T+140C variants (D' = 0.5536). Within African-American subjects, we estimated linkage disequilibrium between the P582S and T+140C sites (D' = 0.0594), the P582S and A-2500T sites (D' = 0.0991), and the A-2500T and T+140C sites (D' = 0.5642).

HIF1A and Associations with V·O2 max
From the identified polymorphisms, we chose to study three in relation to V·O2 max based on their allele frequencies and functional implications: P582S, A-2500T, and T+140C. General subject characteristics are presented in Table 3. All groups that underwent aerobic exercise training exhibited significant increases in V·O2 max (P < 0.05). No groups exhibited a significant change in body weight from baseline (P = 0.12–0.58).


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  		Table 3. Characteristics of the subjects who participated in V·O2 max testing

 
P582S.
As the low frequency of the rare allele in African Americans [p(C) = 0.97, q(T) = 0.03] prohibited meaningful statistical analysis, the results of the analysis of P582S are limited to Caucasian subjects. No significant differences were observed in baseline V·O2 max relative to body weight (ml·kg-1·min-1) among CC and CT/TT genotype groups (24.7 ± 0.36 vs. 24.6 ± 0.67, P = 0.937). Likewise, analysis of absolute V·O2 max (l/min) revealed no significant differences among the same genotype groups (2.01 ± 0.03 vs. 2.05 ± 0.05, P = 0.495).

Analysis of absolute V·O2 max after aerobic exercise training revealed a significant age by genotype interaction in the response to aerobic exercise training (Fig. 2A; P = 0.02). No significant differences in absolute V·O2 max were observed among genotype groups when compared at age 55 yr. However, significant differences were observed in absolute V·O2 max among genotype groups when compared at age 60 yr (Fig. 2A; P = 0.012) and age 65 yr (Fig. 2A; P = 0.005). The same pattern was observed in the analysis of the change in absolute V·O2 max after aerobic exercise training, with data presented in Fig. 2B.



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  		Fig. 2. Absolute V·O2 max (l/min) values after aerobic exercise training (A) and change in absolute V·O2 max (l/min) after aerobic exercise training (B) for Caucasians grouped by HIF1A P582S genotype. Data are adjusted least squares means ± SE. *Significant difference between P582S genotype groups (P = 0.012). {dagger}Significant difference between P582S genotype groups (P = 0.005). {ddagger}Significant difference between P582S genotype groups (P = 0.006).

 
When V·O2 max relative to body weight (ml·kg-1· min-1) was analyzed, the results were quite similar, showing a tendency for an age by genotype interaction (P = 0.06). At age 55 yr, CC and CT/TT genotype groups showed no significant difference in V·O2 max relative to body weight (28.6 ± 0.34 vs. 27.9 ± 072, respectively, P = 0.32). However, when CC and CT/TT genotype groups were compared at age 60 yr (28.7 ± 0.32 vs. 26.5 ± 0.68, respectively, P = 0.005) and at age 65 yr (28.8 ± 0.48 vs. 25.1 ± 1.17, respectively, P = 0.006), significant differences in V·O2 max after exercise training were observed. The same observations were noted in the analysis of the change in V·O2 max relative to body weight after aerobic exercise training, with no significant difference observed among CC and CT/TT genotype groups at age 55 yr (4.0 ± 0.30 vs. 3.2 ± 0.72, respectively, P = 0.32), whereas differences were observed among genotype groups at age 60 yr (4.0 ± 0.32 vs. 1.8 ± 0.68, respectively, P = 0.005) and at age 65 yr (4.0 ± 0.48 vs. 0.5 ± 1.2, respectively, P = 0.006).

A-2500T.
African-American subjects exhibiting the rare T-allele (AT/TT genotypes) at the A-2500T locus were found to have significantly lower baseline V·O2 max relative to body weight (ml·kg-1·min-1) than those homozygous for the common A-allele (Table 4; P = 0.033). There was a tendency for the same relationship when absolute baseline V·O2 max (l/min) was analyzed (Table 5; P = 0.07). After 6 mo of exercise training, no differences in absolute V·O2 max or V·O2 max relative to body weight were observed between the AT/TT and AA genotype groups when covaried for baseline V·O2 max (Table 4).


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  		Table 4. V·O2 max values for African Americans grouped by HIF1A A-2500T genotype

 

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  		Table 5. V·O2 max values for Caucasians and African Americans grouped by HIF1A T+140C genotype

 
T+140C.
As the allele frequencies were dissimilar in Caucasians and African Americans for the T+140C variant, separate analyses were performed by race, and genotype grouping was different for each race, with data presented in Table 5. No significant differences were observed between CC and CT/TT genotype groups in African Americans for V·O2 max before or after aerobic exercise training. Likewise, analysis of V·O2 max in Caucasian subjects revealed no significant differences before or after aerobic exercise training between TT and CT/CC genotype groups.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 References
 
The present study has identified several novel polymorphisms in HIF1A with race-specific allele frequencies, and we examined three of those polymorphisms in relation to V·O2 max before and after 24 wk of aerobic exercise training. The results of these analyses suggest that specific variants in the sequence of HIF1A are associated with differential levels of V·O2 max in older human subjects. The effects of these variants on the expression of HIF1{alpha} mRNA and protein have yet to be determined, and the exact mechanisms underlying these relationships will need to be further explored.

Previous research in a rat model has shown that the increase in HIF1{alpha} protein expression in response to aerobic exercise in normoxic environmental conditions is greater than the increase in response to a hypoxic environment at rest (24). When combining the two stimuli (i.e., aerobic exercise in a hypoxic environmental condition), the level of HIF1{alpha} protein expression was no greater than that due to aerobic exercise alone (24). To our knowledge, this has not been confirmed in human subjects, as we could identify no studies examining protein levels of HIF1{alpha} or HIF1 in humans. Studies in humans have shown no significant increase in HIF1{alpha} mRNA in response to an exercise stimulus (7, 8, 23), but these negative findings may be limited by the intensity of the exercise stimulus and/or the timing of measurements.

Even if the expression of HIF1{alpha} mRNA is not subject to the influence of acute aerobic exercise, HIF1 and HIF1{alpha} protein levels are subject to posttranslational regulation by oxygen tension. Under normoxic conditions, the half-life of HIF1 is less than 1 min (26), but when subjected to low oxygen tension (<30 Torr), HIF1 protein levels increase exponentially (11). Although no publications to date have described differential expression of HIF1{alpha} as a result of genetic variation in HIF1A, such variation has the potential to influence basal HIF1{alpha} mRNA expression and the downstream proteins HIF1{alpha} and HIF1. We would expect that slight variations in baseline expression of these proteins would be amplified when a hypoxic stimulus (i.e., aerobic exercise) is present. The amplification of any such differential expression may result in different levels of HIF1 protein that affect the transcription and expression of downstream target genes, impacting phenotypes such as V·O2 max.

Analysis of V·O2 max among A-2500T genotype groups in African Americans yielded somewhat paradoxical results. Subjects with one or two copies of the rare T-allele (AT or TT genotype) exhibited significantly lower V·O2 max before exercise training than subjects homozygous for the common A-allele (AA genotype). If that difference was the result of differential expression of HIF1{alpha}, then we would expect that the subjects homozygous for the A-allele would have exhibited a greater increase in V·O2 max after aerobic exercise training than subjects with the T-allele. However, the AA and AT/TT genotype groups were found to have increased V·O2 max to a similar degree. Although these findings may be a result of a small sample size, it is clear that further investigation is necessary to determine the nature of this relationship.

Perhaps the most interesting finding in these analyses was the presence of an age by P582S (C/T) genotype interaction in the response of V·O2 max to aerobic exercise training. This interaction indicates that there may be differential responses of V·O2 max to aerobic exercise training as a function of age. Noncarriers of the T-allele (CC genotype) showed preservation of the ability to increase V·O2 max through aerobic exercise training by 4.0 ml·kg-1·min-1 at each age level evaluated. Contrary to this, subjects carrying the T-allele (CT/TT genotype) were able to increase V·O2 max to a similar extent as noncarriers at 55 yr of age, but showed less increase in V·O2 max to aerobic exercise training than noncarriers at 60 and 65 yr of age. We speculate that the differential response of V·O2 max in these subjects may be the result of the predicted change in the amino acid sequence of HIF1{alpha}. Because of the unique chemical structure of proline, replacement with serine (T-allele) at amino acid 582 may affect HIF1{alpha} structure and function. Although any further attempt to explain the mechanism behind this interaction would be imprudent, these findings clearly warrant further investigation into the role of the HIF1A P582S polymorphism, particularly with advancing age.

Based on the results of this study, we conclude that sequence variation in HIF1A appears to be associated with differential levels of V·O2 max in older adults before and after a standardized program of aerobic exercise training, particularly the P582S polymorphism in older Caucasian subjects and the A-2500T polymorphism in older African-American subjects. Considering this and the previously established physiological role of HIF1{alpha}, it seems valuable to further investigate the role of HIF1A variants in determining baseline V·O2 max and the response of V·O2 max to aerobic exercise training. Further investigation should be conducted in a variety of age groups to fully understand the associations of HIF1A genotype with V·O2 max across the aging spectrum. Beyond that, it is important to determine whether HIF1 protein or HIF1{alpha} mRNA or protein levels differ as a result of HIF1A genotype. Moreover, evaluation of the influence of acute and chronic aerobic exercise in normoxic environmental conditions on HIF1 and HIF1{alpha} expression should be undertaken to better understand the role of HIF1{alpha} in determining V·O2 max.


   DISCLOSURES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
References
 
S. J. Prior was supported by the David H. Clarke Fellowship in the Department of Kinesiology at the University of Maryland. This study was funded by National Institutes of Health Grants AG-15389, AG-17474, AG-05893, and DK-46204.


   ACKNOWLEDGMENTS
 
We thank the volunteers who participated in the study. Nancy Petro and Mechele Lee provided important technical assistance.


   FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: S. M. Roth, Functional Genomics Laboratory, Dept. of Kinesiology, Univ. of Maryland, 2134 HHP Bldg., College Park, MD 20742 (E-mail: sroth1{at}umd.edu).

10.1152/physiolgenomics.00061.2003.


   References
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 References
 

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