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J Appl Physiol 97: 72-76, 2004. First published February 27, 2004; doi:10.1152/japplphysiol.01087.2003
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Human ACE I/D polymorphism is associated with individual differences in exercise heat tolerance

Yuval Heled,1 Daniel S. Moran,1 Liran Mendel,1 Arie Laor,1 Elon Pras,2 and Yair Shapiro1

1Heller Institute of Medical Research, and the 2Danek Gartner Institute of Human Genetics, Tel Aviv University, Sheba Medical Center, Tel Hashomer 52621, Israel

Submitted 7 October 2003 ; accepted in final form 20 February 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We hypothesized that there is an association between the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism with the variability in exercise heat tolerance in humans. Fifty-eight Caucasian men were exposed to a 2-h exercise heat-tolerance test. We analyzed the association between their heat-tolerance levels with the ACE DD (n = 25) and I+ (n = 33) genotypes and with various anthropometrical parameters and aerobic fitness. It was found that the relative changes in body core temperature, heat storage, and heart rate during the 120-min exposure to exercise heat stress was consistently lower in the I+ genotype group compared with the DD genotype group (0.8 ± 0.2 vs. 1 ± 0.1°C, P < 0.05; 17.7 ± 1.8 vs. 19.8 ± 1.3 W/M2, P < 0.05; and 33 ± 7 vs. 44 ± 5 beats/min, respectively, P = 0.06). No significant association was found between heat strain response and the anthropometrical measurements or aerobic fitness in the various genotype groups. We suggest that the ACE I+ polymorphism may be considered as a possible candidate marker for increased heat tolerance.

angiotensin-converting enzyme polymorphism; thermoregulation; exercise; heat stress; genetics

PHYSICAL EXERCISE INCREASES the rate of metabolic heat production and therefore, especially when performed in a hot environment, may cause hyperthermia and even fatal heat stroke (7). To prevent hyperthermia, the balance between heat gain (metabolic and environmental) and heat dissipation must be maintained. Optimal balance in humans requires an efficient thermoregulatory system, which is mainly based on cardiovascular and sudomotor (sweating) functions (12). However, it was found that, in a normal thermoregulatory response to exercise heat stress, there is a wide range of variability (9, 15). Those individuals having a more-severe heat-strain response to exercise in hot environments are defined as less tolerant to heat (9). The variability in heat tolerance in healthy humans has been shown to be related to gender (29, 30), physical aerobic fitness (11, 17), and anthropometric measurements (16). Nevertheless, it has been shown that, even after adjustment of these phenotypic factors, individual differences in heat-stress response still exist (14). Those individuals, especially among the young active population (athletes, soldiers, laborers), who are more susceptible to hyperthermia, are at risk to contract heat injuries.

When phenotypic characteristics fail to explain the variability in heat-stress response, genotype characteristics become an attractive candidate. To the best of our knowledge, no study has yet directly characterized a possible genotype association with heat tolerance in human or animal models.

Over the last few years, some studies have suggested that the DNA sequence variation at the gene locus encoding angiotensin (ANG)-converting enzyme (ACE) is associated with physical performance (10, 28) as well as with a number of pathological processes (4). Although still controversial, it was reported in a series of papers that the insertion (I) allele of the I/deletion (D) polymorphism in intron 16 of the ACE gene is associated with better endurance performance, whereas the DD genotype is associated with lower endurance performance (10, 24, 28) and higher cardiovascular morbidity (1, 3, 4). The DD genotype was also found to be associated with the highest plasma levels of ACE, whereas the II polymorphism had the lowest levels of ACE (20, 32).

ACE is part of the renin-ANG system (RAS), which is found in both the circulation system (8) as well as various tissues (4, 22). RAS is known to have an important role in thermoregulation via its influence on vascular mechanisms and fluid balance (8, 18, 19). Although several studies pointed to the possible influence of ACE on endurance performance and the important role of this enzyme in thermoregulation (19, 22), no study has directly analyzed the possible association between ACE genotypes to individual differences in heat-stress response. We therefore hypothesized that it may be associated, directly or indirectly, with heat-stress response. Therefore, to evaluate the potential contribution of the ACE genotype on heat-stress response, we analyzed the association between the different ACE genotypes with the variability in exercise heat-stress response in humans. Such an association may be an important marker, together with other phenotypic (and probably genotypic) factors, for predicting heat tolerance. Because of the reported advantage of the I allele with cardiovascular function as well as metabolic efficiency (28), we hypothesized that the existence of the I allele would be associated with better thermoregulatory function and, therefore, with better heat-stress response.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Fifty-eight healthy Caucasian male volunteers participated in the study. Their physical characteristics were (mean ± SD), age 22 ± 1 yr, height 174 ± 7 cm, weight 73 ± 11 kg, body mass index 24 ± 3 kg/m2, body surface area 1.8 ± 0.15 m2, and body fat 16.5 ± 5%. All subjects gave informed consent before participation and went through a medical examination. The study was approved by the health ministry committee of human genetic studies.

The volunteers arrived at our institute on 3 consecutive days at 0800.

On day 1, they went through a medical examination and anthropometric measurements, which included weight, height, and percent body fat. Body fat was measured by multiple skinfold-thickness measurements that were performed by one experienced researcher. The mean of two skinfold-thickness measurements made with calipers at each of two sites (triceps and subscapular) (21) was calculated to assess percentage of body fat. Body mass index was calculated as weight (kg) divided by height (m). Body surface area (in m2) was calculated as W0.425·h0.725·0.007184, where W is weight (in kg) and h is height (in cm) (6). Nine milliliters of blood were taken from each subject for genetic analysis. On day 2, the volunteers performed a maximal oxygen consumption test to evaluate their aerobic fitness. Maximal oxygen consumption was determined by using online computer-assisted open-circuit spirometry (Sensor Medics, Yorba Linda, CA) during incremental exercise on a motorized treadmill. Volunteers ran on the treadmill (5.5–6 miles/h), with the grade being increased every 2 min by 2.5%. A valid maximal oxygen consumption was accepted when at least three of the following criteria were met: 1) a plateau in oxygen consumption with increasing work rate, 2) a respiratory exchange ratio at maximal exercise of >1.10, 3) achievement of age-predicted maximal heart rate (HR; 220 – age), and 4) subjective exhaustion. Anaerobic threshold, which is an important factor in aerobic fitness, was determined according to the minute ventilation-to-oxygen consumption ratio dynamics and from the respiratory exchange ratio ({cong}1).

On day 3, subjects performed a heat-tolerance test to evaluate their physiological response to exercise heat stress. All tests were performed in the win order to prevent the effects of natural heat acclimatization. Heat-tolerance test included walking on a treadmill (3.5 miles/h) under heavy heat load (40°C, 40% relative humidity) for 2 h in a climatic chamber. During heat exposure, rectal temperature (Tre) was continuously measured by a rectal thermistor YSI-401 (Yellow Springs Instruments) inserted 10 cm beyond the anal sphincter. Skin temperature (Tsk) was continuously measured at three sites (arm, chest, and leg) with skin thermistors (YSI-409). Mean Tsk was calculated according to Burton's equation (2): Tsk = 0.5Tchest + 0.34Tleg + 0.16Tarm, where Tchest, Tleg, and Tarm are the temperatures of the chest, leg, and arm, respectively. All measurements were continuously recorded by a computerized system (Envidas, Envitech, Israel) and displayed online on a screen. HR was continuously monitored by a heart watch with data logger (Polar, Stamford, CT).

Average heat storage (S) in W/m2 was calculated from the equation S = [(mb·cb)/AD]·({Delta}Tb/{Delta}t), where mb is the mean body weight (in kg); cb is the specific heat constant (0.965 W·h–1·°C–1·kg–1); AD is Dubois body surface area; {Delta}Tb is the change in mean body temperature (°C), where Tb = 0.2Tsk + 0.8Tre; and {Delta}t is the exposure time (in h) (13). Physiological strain index, based on Tre and HR and calculated on a universal scale of 0–10 (26), was calculated at 10-min intervals to assess the relative level of heat strain as 5(Tret – Tre0)·(39.5 – Tre0)–1 + 5(HRt – HR0)·(180 – HR0)–1, where Tret and HRt are simultaneous measurements taken at any time during heat exposure, Tre0 and HR0 are the initial resting values, and 39.5 and 180 represent maximal core temperature (°C) and HR (beats/min), respectively. Sweat rate (in g/h) was calculated according to the difference between pretest and posttest nude body weight, with the posttest weight corrected for fluid input and urine output, divided by the time of exposure.

Exclusion criteria.   Any one of the following criteria was used for removal of a subject from heat exposure: Tre of >39°C, HR of >170 beats/min, nausea, weakness, dizziness, subject's request, or the decision of the physician in charge.

The volunteers were instructed to rest for at least 3 days before the experiment and to drink 0.5 liter of noncaffeine beverages on the night before and on each morning of the experiment to ensure body euhydration. Throughout the exercise period, subjects were allowed and encouraged to drink ad libitum.

DNA was extracted from peripheral leukocytes (obtained from 3 ml of peripheral blood drawn into EDTA-containing tubes) by using Puregene DNA purification kit (Puregene, Gentra systems). DNA concentration was calculated from absorbance at 260 nm measured by an Ultraspec 2000, UV/VIS spectrophotometer (Amersham Pharmacia Biotech). Purity was estimated by the ratio of absorbance at 260:280 nm.

Screening for the ACE I/D polymorphism was done by PCR. A set of primers were designed to amplify the fragment encompassing the I/D polymorphism (the sense and antisense primers were 5'-TGGGACCACAGCGCC CGCCACTAC-3 and 5'-CTGGAGACCACTCCCATCCTTTCT-3', respectively).

The PCR 190-bp fragment for the D allele and 490-bp fragment for the I allele were separated by electrophoresis with 2% agarose gel (Tamar) and visualized by ethidium bromide staining. As opposed to other studies (5), there was no difficulty in distinguishing between the DI and DD allele due to preferable amplification. Therefore, the three-primer method was not used in this study. We focused in our analysis on the possible difference in the association between the heat-strain response to the existence of the ACE I allele (I+) compared with the DD genotype.

Statistical analysis.   The significance of differences between continuous variables was assessed with Student's t-test. The pooled form of statistics tested equality of variance; correction for unequal variances was performed when appropriate. All tests of significance were two tailed. Pearson correlation coefficients were used to analyze the interrelationship between anthropometric, physiological, and genetic variables. The relative contribution of the variability of the physiological, anthropometric, and genetic factors to heat tolerance was analyzed by multiple regression analysis. The independent variables used in the model were anthropometric, physiological, and genetic data recorded before the exercise heat exposure. A stepwise selection method was used to delineate a set of contributory variables to the variability of risk factors. Variables were added one by one to the model, and the F statistics for a variable to be added had to be significant at the 0.15 level. After a variable was added, the stepwise method looked at all the variables included in the model and deleted any variable that did not produce an F statistic significant at the 0.05 level. Only after this assessment was made and the necessary deletions accomplished could another variable be added to the model. The stepwise process ended either when none of the variables outside the model had an F statistic significant at the 0.15 level, when every variable in the model was significant at the 0.05 level, or when the variable to be added to the model was the one just deleted from it. The relative contribution of an independent (predictor) variable to the relative change of a risk factor was measured by partial squared correlation. The significance of the genotype distribution was assessed by {chi}2 test. All data are presented as means ± SE. The data were analyzed by PROC REG of SAS 8.2 software.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
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The anthropometrical and physiological results of the two genotype study groups (DD and I+) are presented in Table 1. No significant differences were found in the anthropometrical and physiological characteristics between the groups. It should also be emphasized that no differences in these characteristics were found between the three genotype groups (DD, DI, and II) (data not shown). Genotype frequencies of the genotype groups were in Hardy-Weinberg equilibrium, making selection bias less likely.


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  		Table 1. Anthropometrical and physiological characteristics of the DD and I+ genotype groups of the ACE gene

 
The associations between the two genotypes and the various physiological heat-stress responses are presented in Table 2. No significant differences were found in the baseline physiological measurements (Tre0, Tsk0, HR0) before exposure to exercise heat stress. However, after 120 min, all the physiological measurements that express heat-strain level were higher in the DD genotype group compared with the I+ genotype group (although for the Tre P value was only 0.08). When the differences between the physiological measurements at baseline to the end of the exercise period were calculated, it was clearly confirmed that heat strain was higher in the DD group compared with the I+ group. Calculated heat storage during the exposure was also significantly higher in the DD group compared with the I+ group. Worth noting, physiological strain index was higher in the DD group compared with the I+ group, although not significantly.


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  		Table 2. Association between the 2 ACE genotype groups with the baseline physiological levels and the physiological heat-strain responses after exposure to a 120-min exercise heat stress

 
When comparing the dynamics of Tre (Fig. 1) and HR (Fig. 2) during the 120 min exercise heat exposure, we can see that the differences in the physiological strain between the two genotype groups is salient after the first 20 min and throughout the reminder of the exposure period.



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  		Fig. 1. Dynamics of heart rate during the 120-min exposure to exercise heat stress in the 2 genotype groups (DD and I+). bpm, Beats/min.

 


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  		Fig. 2. The dynamics of rectal temperature (Tre) during the 120-min exposure to exercise heat stress in the 2 genotype groups (DD and I+).

 
Analysis of possible association differences between the three genotype groups (DD, DI, II) pointed to the same trend of results (Table 3). However, the small sampling did not allow for a significant statistical analysis.


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  		Table 3. Association between the 3 ACE genotype groups with baseline physiological levels and the physiological heat-strain responses after exposure to a 120-min exercise heat stress

 
No association was found between any of the baseline anthropometrical and physiological parameters (Table 1) to the various genotypes.

None of the subjects was excluded from the study.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we have shown for the first time that the existence of the I allele (I+) of the human ACE gene is associated with increased heat tolerance during exposure to exercise heat stress. It was also found that the homozygosity of the II allele had the best heat-tolerance results. This group was very small, however (n = 7), so statistical analysis could not significantly support this result, although there was definitely a dose effect of the existence of the I allele.

Although various studies have pointed to the association of the ACE I allele with better endurance training effects and performance (24), similar to other studies (31), no significant association between aerobic fitness and the ACE genotype was found in the present study.

Aerobic fitness and body morphometry are known as important factors in determining exercise heat tolerance (16, 33). Because no differences were found in these factors between the study groups and no association was found between any of these factors to the heat-strain response, it may be suggested that the effects of the ACE genotype on exercise heat-stress response do not result indirectly from higher aerobic fitness and/or differences in body composition. Although we can point to some possible mechanisms, it should be emphasized that, at this point, any attempts to clearly explain an association of the ACE I/D polymorphism with heat tolerance must remain speculative. ACE is an important part of the RAS system. This system, which is found in both the circulation (8) as well as various tissues (4, 22), has been shown to play an important role in thermoregulatory responses to exercise heat stress (8, 18, 19). Tissue RAS is part of the mechanisms that are responsible for precise matching of tissue blood flow, tissue oxygenation, tissue work, and tissue growth, whereas the circulating RAS, consisting of secretion of kidney-derived renin into the systemic circulation, mainly provides control of blood pressure (28). The effect of ACE genotype on heat tolerance might be mediated through several different mechanisms. In the systemic endocrine level, the mechanism may be associated with the different plasma levels of ACE and, therefore, of ANG II in the different genotype groups. It has been reported that DD polymorphism is associated with higher serum ACE and, therefore, with higher ANG II levels, which might be connected to increased susceptibility to high blood pressure and cardiovascular morbidity (3, 4). Because the vasomotor function has an important role in the thermoregulatory mechanism (25), the vulnerability to cardiovascular morbidity, and therefore to decreased function, might be a possible explanation for the mechanism by which different ACE genotypes influence the thermoregulatory response to exercise heat stress. It is interesting to note in this context that, although significant differences were found in most parameters of heat stress response, no differences were found in sweat rates between groups. This fact may strengthen our hypothesis regarding the advantage of the cardiovascular function in the I+ group. Because no changes in the evaporation rate are expected between groups, the main candidate mechanism that influences the thermoregulatory function is the cardiovascular system. It is also interesting to note, in this context, that administration of ANG II blockade to six men and three women in another study was not found to impair the thermoregulatory responses during exercise in the heat (23). These results may weaken our present suggested mechanism, although, scientifically, use of acute administration of the drug cannot necessarily be compared with our methodology, results, and mechanisms. It should also be mentioned that a different hypothesis was previously published (27). This hypothesis claimed that the ACE DD polymorphism, which may be associated with the predisposition to hypertension in sub-Saharan Africans, is also responsible to their better survival in extreme heat conditions. This hypothesis, however, dealt with a specific ethnic group with no suggested mechanisms.

In the central system, RAS has been found to have a local influence on the brain thermoregulatory center (18, 22). Although not yet extensively studied, ACE polymorphism, therefore, might play a role in this regulatory level as well.

It has been suggested that in muscle tissue local RAS had an important metabolic effect and a lower ACE activity, such as in the existence of the I allele (4), which improves muscle metabolic efficiency (28). We suggest, therefore, that this mechanism may also be associated with reducing exercise heat-stress response.

It is interesting to note, however, that the increased metabolic efficiency was not expressed in aerobic fitness of the different genotype groups in the present study. We therefore suggest that, because aerobic fitness only partly influences heat tolerance, this genotype may be at an advantage, especially during situations of high heat stress.

Although various possible mechanisms have been suggested, it should be noted that the thermoregulatory process involves complex mechanisms and probably results from multifactorial polygenic characteristics with the ACE genotype only being a part of them. These assumptions should be further studied.

Our data should also be interpreted with caution, because not all of the results were significant (although the trend was definitely consistent), the sample was relatively small, and only Caucasian men were studied.

In conclusion, it is proposed that a genetic factor associated with the ACE I allele in young Caucasian men might provide an advantage during exercise heat stress. More studies are required to decide whether the existence of the ACE I allele may be a candidate prediction marker for better tolerance to exercise heat stress.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y. Heled, Heller Inst. of Medical Research, Sheba Medical Center, Tel Hashomer 52621, Israel (E-mail: yheled{at}sheba.health.gov.il).

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.


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