Abstract
Angiotensin-converting enzyme (ACE) gene has been reported to be one of the candidate genes for endurance performance. The ACE gene insertion/deletion (I/D) polymorphism (rs4646994) is responsible for the variation in the ACE plasma level. The insertion (I allele) of ACE I/D gene polymorphism decreases the level of ACE plasma, thus reducing skeletal muscle vasoconstriction. Skeletal muscle vasoconstriction increases oxygenated blood supply to working muscles for endurance performance. On the other hand, the D allele of ACE I/D gene polymorphism increases the level of ACE plasma, leading to skeletal muscle hypertrophy. Therefore, the D allele may be helpful for strength or power performance. However, evidence for the involvement of these alleles in improving endurance performance and muscle strength is inconsistent and warrants further studies. These inconsistencies may be attributed to the small sample size and the potential causes of the racial and ethnic differences used in the previous studies. Therefore, this brief review reported a summary of the current literature on the association of the ACE I/D gene polymorphism on human physical performance across populations. The findings of this review may serve as a reliable platform and guidance for future research to provide a better understanding of the potential role of this variant on human physical performance concerning ethnicity.
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Introduction
Athletic performance may be affected by various factors, such as skills, training, and genetics. Among these factors, the genetic factor is more likely to have a significant effect on athletic performance, as it influences innate human ability [1]. For instance, Pérusse [1] provided strong evidence that the genetic factor significantly contributes to performance-related traits, including cardiorespiratory endurance and muscle strength. Additionally, the genetic factor accounts for 40–60% variations in aerobic and cardiac functions, 50–90% variations in anaerobic performance, 30% to 70% variations in muscular fitness, and 20–30% variations in cardiac performance [1]. Genetic influence on the physical trait is important for endurance performance, especially for an athlete to excel in sports. For example, sprint performance depends on genetic factors that adapt the body to build strong leg muscles. This body adaptation provides the athlete with several advantages, such as overcoming inertia at the beginning of the sprint, taking long strides, and allowing the calf muscles to work effectively for sprint acceleration [2].
It is an intricate task to understand the genetics of human performance. Solomon et al. [3] defined genetics as a branch of science that studies heredity (genes) and how individuals inherit and transfer the genetic traits from one generation to the next. In other words, humans inherit hereditary characters such as height and skin colour from their parents. A gene is a fundamental component in genetics [4], and it is a part of deoxyribonucleic acid (DNA) that contains particular codes to synthesise a specific protein [5]. The protein is used to build tissues, organs, and finally, an organism [5]. The primary sequence of DNA molecules in the gene sequence encodes the information needed to synthesise a specific protein in the human body [6]. Genes are substantially different in size, where the size ranges from less than 100 base pairs to more than several million base pairs [6]. Many genes exist in various forms (known as an allele) due to mutation that affects the DNA base sequence [7]. Every person has two copies of the alleles of a given gene, whereby each allele is inherited from each parent [7]. Each allele of a given gene (at the same locus or position on the chromosome) has minor differences in its DNA base sequence [7]. Each pair of alleles is the genotype of a specific gene that expresses an individual’s phenotype [6]. An individual that carries the same pair of alleles of a given gene is called homozygous [7]. On the contrary, an individual with a different pair of alleles is called heterozygous [7]. Additionally, different versions of alleles contribute to the various phenotypes or physical characteristics [7]. For instance, previous studies suggested that the differences in physical performance between athletes and non-athletes may be due to genetic variations in specific allele genes [7]. In the future, the knowledge about an individual’s genetic profile will help both athletes and coaches to identify the right sports discipline and prepare a personalised athlete training programme.
Several studies have shown a link between specific genes or variants and human physical performance [8,9,10]. Additionally, the findings from twin studies (controlled for environmental factor) demonstrated that genetic was the main factor that contributed to the physical characteristic needed for a specific sport [11,12,13,14]. To date, 239 genes consisting of 214 autosomal gene entries, plus seven other on the X chromosomes, and 18 mitochondrial genes have been associated with sports performance [15]. Among these candidate genes, it has been suggested that the angiotensin I-converting enzyme (ACE) gene is the most potent candidate gene-related to endurance performance [16].
The ACE gene
In humans, the ACE gene can be found on the long arm (q) of chromosome 17 (17q23.3). As shown in Fig. 1, this gene is 21 kb long and consists of 26 exons and 25 introns [17]. The ACE gene produces ACE [17], which is a key element in the renin-angiotensin (RAS) system that regulates blood pressure, water fluid balance, and tissue growth [18]. In a circulating RAS system, the primary role of ACE is to produce angiotensin II (ANG II) [19], as illustrated in Fig. 2. The ANG II is a potent vasopressor and aldosterone that stimulates angiotensin I peptide (ANG I) [19]. In addition, the ANG II decomposes bradykinin, which is a potent vasodilator [19]. It is also important to note that each individual has different levels of ACE in plasma. However, family members have a similar level of ACE plasma, suggesting that the interindividual variability in the ACE plasma level is determined by genetic factors [20]. Among several polymorphisms of the ACE gene, the ACE I/D gene polymorphism (rs4646994) has a strong association with the ACE plasma level, which accounts for 47% of the overall phenotypic variance of the ACE activity [21] (Figs. 1, 2).
The ACE I/D gene polymorphism
The polymorphism of the ACE I/D gene refers to the insertion (I allele) or deletion (D allele) of 287 base pairs in intron 16 of chromosome 17 [22]. The ACE level in people with two copies of the I allele was reported to be low [21]. The reduced level of ACE led to a decrease in the conversion of ANG I to ANG II, which resulted in less vasoconstriction and increased oxygenated blood circulation to the working muscles [17, 23]. Conversely, individuals with two copies of the D allele had a high ACE level [21]. A high ACE level resulted in a higher ANG II level, increased vasoconstriction, and reduced oxygenated blood flow to the working muscles [17, 23].
The ACE I/D gene polymorphism has three genotypes: (i) the II genotype (low serum ACE levels), (ii) the ID genotype (intermediate ACE serum levels), and (iii) the DD genotype (high ACE serum levels) [21]. Several studies that examined the distribution of ACE I/D gene polymorphism have shown that the allele and genotype frequencies vary across different racial groups [24,25,26,27].
The distribution of ACE I/D gene polymorphism across ethnicity
There has been a difference in the distribution of the ACE I/D gene polymorphism in various racial and ethnic groups in the current literature (Table 1). Among the racial groups, the Black (Australian Aboriginal) population has the highest frequency of the I allele (0.97) [28], whereas the Caucasian population has the highest frequency of the D allele (0.77) [29]. The distribution patterns of the I and D alleles in the Black community were approximately 0.97 to 0.27 and 0.73 to 0.03, respectively. Additionally, the Australian Aboriginal minority ethnic group in the Black population was found to have the highest prevalence of I allele than other Black ethnic groups [28]. Also, the D allele was the most common among Nigerians [25] and Somalis [30]. The trend among Amerindians [31], on the other hand, was closely similar to that of Pima Indians [32], Coastal Papua New Guineans [33], Sothos [34], Mulattos [35], and Alaska Natives [34].
For the Caucasian population, the concentrations of I and D alleles ranged from 0.78 to 0.23 and 0.77 to 0.22, respectively. Among the Caucasians, the highest frequency of the I allele was observed for the Mexicans [31], whereas the highest frequency of the D allele was observed for the Europeans [29]. Nevertheless, the presence of I allele was uncommon among the European [29] and the Middle East populations, such as the Egyptians [36] and Omanis [37]. Besides, the presence of I allele among Mexicans [31] was observed to be closely related to the European population [38]. Also, the highest frequency of the D allele observed among Europeans [29] was relatively similar to that reported for Egyptians [36] and Omanis [37]. The ACE I/D gene polymorphism trend in the Australian population [28, 39] was the same as that reported for the Brazilian [35] and European [40] populations. Nevertheless, findings from several studies of the same ethnic group, such as Turkish, have been consistently similar [41,42,43,44]. However, research on the European population has shown inconsistent results. For example, the frequency of the I allele in the European population reported by Cambien et al. [38] was inconsistent with other studies; 0.23 [29], 0.43 [45], and 0.51 [26].
In the Asian population, the I and D alleles ranged from 0.76 to 0.42 and 0.58 to 0.24, respectively. The highest frequency of the I allele was observed for the Javanese ethnic group [46], whereas the highest frequency of the D allele was observed for the Kazakh ethnic group [47]. In a study by Jayapalan et al. [27], they investigated the various ethnic groups in Malaysia. It was observed that the highest frequency of the I allele was among the Malays, whereas the highest frequency of the D allele was among the Indians [27]. Furthermore, the frequency of the I allele observed among the Malays was significantly comparable to Thai [48], Singaporean Chinese [49], and Javanese [46]. In contrast, the frequency of the D allele observed among the Malaysian Indians was equivalent to other Indian ethnic groups in Asia [50, 51].
The trend observed among the Chinese population in Malaysia has also been significantly similar to the trend observed for the Hong Kong Chinese [52], Taiwanese [53], and Japanese [54]. The study by Yusof et al. [55] on the Malaysian population supports previous findings on ACE I/D gene polymorphism distribution across ethnic groups. Specifically, Yusof et al. [55] found that both the Malay and Chinese ethnic groups had a higher frequency of the D allele than the Indian and other native groups. The results reported by Yusof et al. [55] differ from the previous study carried out on the Malaysian population [27]. Additionally, Yusof et al. [55] reported that the frequency of the I allele in the Malaysian population was highest among the Malay ethnic group (0.66), followed by the Chinese ethnic group (0.53), Indian ethnic group (0.46), and the lowest frequency in the other native groups (0.41). The distribution pattern of ACE I/D gene polymorphism reported by Yusof et al. [55] for the Malay ethnic group was remarkably similar to that of Japanese [56] and Taiwanese [53] populations. The frequency of the I allele in other native groups was among the lowest reported among Asians and was similar to the rate observed among the Caucasian population [42, 57]. Concerning current evidence for ACE I/D gene polymorphism, ethnicity appears to play an essential role in the distribution of ACE I/D polymorphism, as suggested by Barley et al. [24]. Overall, these findings indicate that ACE I/D gene polymorphism may have a different effect on human physical performance or health in other populations, as documented for the Caucasian population.
The various distribution patterns of ACE I/D gene polymorphism in different ethnic groups are consistent with the previous studies on the effects of ACE I/D gene polymorphisms on disease sensitivities [54,55,56,57,58,59,60]. For example, Ng et al. [58] found that the association of ACE I/D gene polymorphism with diabetic nephropathy was more prevalent in the Asian population than the Caucasian population. Based on the data from the distributions of ACE I/D gene polymorphism in general populations across the world and research on the effects of ACE I/D gene polymorphism on susceptibility to diseases, it can be assumed that the effect of ACE I/D gene polymorphism on human physical performance may also vary depending on ethnicity. However, this assumption remains inconclusive due to insufficient comparative analysis across ethnic groups [16, 59]. A recent meta-analysis study has shown that the effect of ACE I/D gene polymorphism on human physical performance has been documented mostly for the Caucasian population and less for the Asian population [16].
Therefore, further studies involving the Asian population are warranted to understand the differences of ACE I/D gene polymorphism across ethnic groups. This effort is important as preliminary data indicated that the differential effects of ACE I/D gene polymorphism may influence individual variation in response to training [60,61,62,63,64]. For example, the ACE I/D gene polymorphism has affected adaptation to weight-lifting and walking [64], isometric, and dynamic leg training [61], as well as aerobic exercise [60, 62, 63]. These studies showed that people with the same ACE I/D polymorphism genotype had similar responses to training. Additionally, several studies have shown that blood pressure varies among people with different ACE I/D alleles or genotypes during a health management exercise training [60, 63, 66]. For example, Hagberg et al. [60] showed that the I allele carriers had a lower systolic and diastolic blood pressure after 9 months of exercise training than the D allele carriers [60]. Additionally, the maximum oxygen intake capacity (VO2 max) measured during incremental exercise was 75% to 85% more for the I allele carriers than the D allele carriers [60]. In relation to these findings, more studies should be done to obtain the prevalence data of ACE I/D gene polymorphism in different ethnic groups to confirm the interactive effects of ethnicity and ACE I/D gene polymorphism on human physical performance, especially among the Asian population.
I allele and endurance performance
Several studies have reported the additive effect of I allele on human physical performance. A study by Gayagay et al. [66] on 64 Australian national rowers was the first study to successfully show the additive effect of the I allele on endurance performance. They found that the frequency of the I allele was more prevalent in rowers compared with the controls. In another study, Montgomery et al. [67] reported a similar result for 33 elite high-altitude male mountaineers and 1,906 British military male recruits. They found that the recruits with the II genotype displayed an 11 fold improvement after a 10-week general physical training programme relative to the DD genotype carriers [67]. Since the discovery, the ACE gene has attracted worldwide attention as a candidate gene for endurance performance [3].
The presence of the I allele was more prominent among endurance athletes [68,69,70,71], rowers [66, 72], triathletes [73, 74], and long-distance swimmers [75]. It has also been reported that individuals with the I allele have higher VO2 max [76, 77], higher slow-twitch muscle fibre [78], higher cardiac output [79], and higher heat tolerance [80] compared to individuals with the D allele. Also, some studies have attempted to determine whether the possession of I allele would improve training adaptations. In contrast to the D allele carriers, studies have shown that the I allele carriers can improve their mechanical performance after 11-week of the aerobic training programme [62], enhance aortic distensibility through chronic long-term training [81], increase adherence to 6-month training by 60% and increase the mean exercise capacity by up to 85% [82], and expand training progress up to 6 months [83].
Although the results mentioned above are convincing, the impact of the I allele on endurance performance has not been well-established, as several studies failed to replicate the link between I allele and the status of endurance athletes [84,85,86,87,88,89,90,91]. Moreover, several cross-sectional studies have shown that people with D alleles have better endurance [89] and VO2 max values [92] than those with I alleles. Also, the VO2 max of individuals with the DD genotype increased by 14% to 38% after the exercise training programme compared to those with the II genotype [93].
There is no known reason for these inconsistent findings. The ethnicity factor could be one of the factors that contributed to these inconsistencies. Furthermore, previous reports show that the distribution of ACE I/D gene polymorphism varies between ethnic groups. Therefore, to control for potential bias, population-specific research is warranted to confirm the impact of I allele possession on endurance performance. Furthermore, to date, there are only a few studies on the additive effect of I allele on endurance performance among Asians (e.g. Malaysian population) compared to the Caucasian population [16]. This limited set of data raises the question of whether the effect of I allele possession on endurance performance that was previously reported for Caucasians will also be seen for the Asian population (e.g. Malaysian population). In a previous study, Goh et al. [77] studied the impact of Asian ethnicity (i.e. Singaporean) on the effect of ACE I/D gene polymorphism on aerobic capacity. From the study, it has been suggested that the ACE I/D gene polymorphism can have a universal impact on human physical performance, irrespective of ethnicity.
Nonetheless, Yusof et al. [94] found that the presence of I allele is not a predictor of endurance performance in a multi-ethnic group of Malaysians, although the presence of I allele was consistent with the stamina status among the Malaysian population. This finding was based on the results of the Yo-Yo intermittent level 2 test [94]. Specifically, it was found that the score for the Yo-Yo intermittent recovery level 2 was similar in all three ACE I/D genotype groups [94]. However, the results of Geisterfer et al. [96] contradict those of earlier Asian [77] and Caucasian [83, 95] studies, indicating that individuals with the II genotype have greater durability than those with other genotypes (Table 2).
Given the above findings, future studies may extend the current research by running a larger sample size to confirm the possession of the I allele on endurance performance. Table 2 provides a summary of studies investigating the effect of I allele possession on endurance performance.
D allele and Strength/power performance
The D allele of ACE I/D gene polymorphism was thought to influence strength or power due to the increased level of ACE activity in a person with the D allele [96, 97]. The elevated ACE activity will increase the development of ANG II (a strong growth factor in cardiac and vascular tissue) in the skeletal muscle RAS, which is the potential mechanism for triggering muscle cell growth and hypertrophy [96, 97]. Several studies have, therefore, tried to assess the effect of D allele possession on strength or power output. The D allele carriers have been reported to have the highest muscle strength compared to the I allele carriers [98,99,100]. Additionally, several case–control studies have found that the prevalence of D allele was higher among athletes who participated in strength or power-oriented events [101,102,103,104,105,106].
Montgomery et al. [107] reported an increase in the left ventricular mass in male Caucasian military recruits after ten weeks of physical training. The development of the left ventricle was seen highest in the recruits with the DD genotype compared to other recruits with the II and ID genotypes [107]. The D allele possession may have damage protecting effects on the muscles as subjects with the DD genotype were reported to have lower blood creatine kinase values than other genotype carriers in response to eccentric contractions [108]. In the meantime, Folland et al. [61] reported that young adult men with a D allele have more strength gains after nine weeks of strength training than those with the I allele. Enhanced power following 18 months of walking and lightweight training has also been seen in older people with the DD genotype compared to other genotypes [64].
Taken together, the possession of the D allele on strength performance remains inconclusive as previous studies have shown inconsistent findings [90, 105, 109,110,111,112,113,114,115]. There are no known reasons for these inconsistencies, but they may be due to ethnicity and limited reports on the impact of D allele possession on strength or power performance from Asian populations, such as Malaysia [16]. A study by Yusof et al. [94] on the multiple ethnic groups of the Malaysian population showed that the D allele was over-represented among strength or power athletes compared to other groups of athletes. This finding was consistent with the previous observations from other Asian [104] and Caucasian [100, 101, 116] samples. Additionally, Yusof et al. [94] showed that athletes with the DD genotype exhibited greater leg strength than those with the II and ID genotypes. The results from Yusof et al. [94] were in line with the previous research reporting that the D allele has positive effects on the muscle strength parameters, such as muscle strength [99] and knee extensor strength [64]. These results provide promising evidence that the possession of the D allele could have a beneficial effect on short-term and high-intensity activities. The potential mechanism underlying the positive impact of the D allele possession on muscle strength is through the integration of the ANG II into the skeletal muscle [117]. It has been reported that greater production of local ANG II increases protein synthesis and cell hypertrophy in the skeletal muscle, thereby contributing to the maximum power of muscle contraction [118]. Table 3 summarises the list of studies that examined the effects of the D allele on strength or power output.
Discussion
The present review included the existing literature on the impact of ACE I/D gene polymorphism on human physical performance by considering the ethnicity factor. The distribution of ACE I/D gene polymorphism varies greatly between different ethnic groups. This finding suggests that the effects of ACE I/D gene polymorphism on human physical performance may differ between individuals of different ethnic groups. However, the results of the current literature should be interpreted with caution as other factors can influence the results. The first limitation of the previous studies was the small number of samples included in the analysis. Most studies did not use an adequate number of samples to detect a specified difference. Therefore, the current results cannot be generalised to the population as the sample size is small. The second limitation was that the previous studies did not control for gender. Most studies included both females and males, and therefore, it is not clear whether gender influences the ACE I/D gene polymorphism. The third limitation was that the findings reported in most studies could also be influenced by the exercise impact that masks gene-related effects on physical performance.
Therefore, future studies are needed to ensure that the study participants are sufficiently homogeneous in terms of age, gender, physical characteristics, and health conditions. Additionally, future studies should ensure that the ethnic effects are restricted and ethically regulated. Future studies must also follow the latest genomic studies and training recommendations. All experimental approaches including case studies, cross-sectional studies, and intervention studies must be implemented to demonstrate the relationship between human physical performance and ACE I/D gene polymorphism [119]. To ensure accurate and objective genetic evaluation, the genotype distributions of the ACE I/D gene polymorphism examined must be in Hardy Weinberg equilibrium.
Based on the current literature, future studies should address the following research questions:
1. Does ACE I/D gene polymorphism interact with other variants that affect human physical performance?
2. Does ACE I/D gene polymorphism vary in its effect on human physical performance?
3. What is the potential mechanism behind the impact of ACE I/D gene polymorphism on human physical performance?
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Acknowledgements
The authors thank the Universiti Sains Malaysia for providing facilities that made this review article work possible. This article is a part of the work funded by Universiti Sains Malaysia (304.CIPPT.6315037).
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Ahmad Yusof, H., Che Muhamed, A.M. Angiotensin-converting enzyme (ACE) insertion/deletion gene polymorphism across ethnicity: a narrative review of performance gene. Sport Sci Health 17, 57–77 (2021). https://doi.org/10.1007/s11332-020-00712-9
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DOI: https://doi.org/10.1007/s11332-020-00712-9