Gene–Physical Activity Interactions: Overview of Human Studies

Abstract

Physical activity level is an important component of the total daily energy expenditure and as such contributes to body weight regulation. A body of data indicates that the level of physical activity plays a role in the risk of excessive weight gain, in weight loss programs, and particularly in the prevention of weight regain. Most studies dealing with potential gene–physical activity interaction effects use an exercise and fitness or performance paradigm as opposed to an obesity-driven model. From these studies, it is clear that there are considerable individual differences in the response to an exercise regimen and that there is a substantial familial aggregation component to the observed heterogeneity. Few studies have focused on the role of specific genes in accounting for the highly prevalent gene–exercise interaction effects. Results for specific genes have been inconsistent with few exceptions. Progress is likely to come when studies will be designed to truly address gene–exercise or physical activity interaction issues and with sample sizes that will provide adequate statistical power.

As evidenced by several consensus meetings and expert panel reports (1,2,3,4,5), the body of scientific evidence regarding the effects of regular physical activity and sedentary behavior on risk factors for common diseases, health outcomes, and mortality rates is already impressive and growing. However, the effects of regular exercise and habitual physical activity have been almost always tested and reported in terms of main effects and group differences. Consequently, the interpretations and conclusions have been based on the average effects observed in groups of subjects. While means and main effects are effective and convenient ways to summarize large amounts of data, they do not reflect the extent to which the members of the group do not follow the pattern suggested by the group mean. In fact, there are considerable individual differences in risk factor responses to regular physical activity, even when all subjects are exposed to the same volume of exercise, adjusted for their own tolerance level (6).

Heterogeneity in Responsiveness to Regular Physical Activity

The concept of heterogeneity in responsiveness to standardized exercise programs was first introduced in the early 1980s (7). In a series of carefully controlled and standardized exercise training studies conducted with young and healthy adult volunteers, it was shown that the individual differences in training-induced changes in several physical performance and health-related fitness phenotypes were large, with the range between low and high responders reaching several folds (7,8,9,10,11). However, the most extensive data on the individual differences in trainability come from the HERITAGE Family Study, where 742 healthy but sedentary subjects followed a highly standardized, well-controlled, laboratory-based endurance-training program for 20 weeks. The training program induced several beneficial changes in cardiorespiratory fitness and other cardiovascular and type 2 diabetes mellitus risk factor phenotypes. However, these changes were characterized by marked interindividual differences. For example, the average increase in maximal oxygen consumption (VO_2max) was 384 ml O₂ with a standard deviation of 202 (Figure 1). The training responses varied from no change to increases of >1,000 ml O₂ per minute (6,12,13). Likewise, systolic and diastolic blood pressure measured during steady-state submaximal (50 W) exercise decreased, on average, by 7 and 3.5 mm Hg, respectively (14). However, the responses varied from marked decreases (SBP > 25 mm Hg and DBP > 12 mm Hg) to no changes, or in some cases, even to slight increases (6,14). It should be noted that person- to-person variability in training responses has been observed not only in the HERITAGE Family Study, but also in several other studies and populations (15,16).

Figure 1.

Heterogeneity of the maximal oxygen consumption (VO_2max) training responses in the HERITAGE Family Study.

Heterogeneity of the maximal oxygen consumption (VO_2max) training responses in the HERITAGE Family Study.

This kind of variation is an example of normal biological diversity, is observed in most populations, is beyond measurement error and day-to-day fluctuation, and is potentially very informative in terms of the adaptive mechanisms involved (6,17). We are only beginning to understand the factors contributing to these interindividual differences, but it is quite well documented that the propensity to be a high or a low responder aggregates in families and most likely is influenced by genetic factors. The following sections will provide a brief overview of the current knowledge on genotype-by-physical activity interactions from genetic epidemiology and molecular genetic studies.

Genetic Epidemiology of Genotype–Activity Interactions

A direct experimental way to test genotype-by-environment interactions is to change one environmental/behavioral characteristic in a systematic and controlled fashion and then document the contribution of the genotype to the interindividual differences in response. Such an approach has been used to investigate the role of genotype in the responsiveness of body composition and metabolic phenotypes to long-term negative and positive energy balance in identical twins (18,19) and the genetic basis of cardiovascular and metabolic responsiveness to endurance training in nuclear families (20). In the negative energy balance trial, seven pairs of young adult male MZ twins exercised on cycle ergometers twice a day, 9 out of 10 days, over a period of 93 days while being kept on a constant daily energy and nutrient intake. The mean total energy deficit caused by exercise above the estimated energy cost of body weight maintenance reached about 58,000 kcal (244 MJ). The mean body weight loss was 5.0 kg, ranging from 1 kg to about 8 kg. However, even though there were large individual differences in response to the negative energy balance, subjects with the same genotype were more alike in body composition changes than subjects with different genotypes (Figure 2). The F ratio of the between-pair to the within-pair variances reached 6.8 for body weight and 14.1 for body fat, the intraclass correlation coefficients being 0.74 and 0.87, respectively.

Figure 2.

Intrapair resemblance in the response of identical twins to regular physical activity. The left panel depicts changes in VO_2max and the right panel changes in body weight. See refs. 9 and 19 for details.

Intrapair resemblance in the response of identical twins to regular physical activity. The left panel depicts changes in VO_2max and the right panel changes in body weight. See refs. 9 and 19 for details.

In pairs of MZ twins, the VO_2max response to standardized training programs showed 6–9 times more variance between genotypes than within genotypes (Figure 2) (9). Thus, gains in absolute VO_2max were much more heterogeneous between-pairs of twins than within-pairs of twins. In the HERITAGE Family Study, the increase in VO_2max in 481 individuals from 99 two-generation families of white descent showed 2.6 times more variance between families than within families, and the model-fitting analytical procedure yielded a maximal heritability estimate of 47% (12). In addition to VO_2max, the heritability of training-induced changes in several other phenotypes, such as submaximal aerobic performance (21), resting and submaximal exercise blood pressure, heart rate, stroke volume and cardiac output (22,23,24,25), body composition and body fat distribution (26,27), and plasma lipid, lipoprotein, and apolipoprotein levels (28), has (subject is heritability) been investigated in the HERITAGE Family Study. The maximal heritabilities for these traits ranged from 25% to 55%, further confirming the contribution of familial factors to the person-to-person variation in responsiveness to endurance training.

Molecular Genetic Studies

The evidence from the genetic epidemiology studies suggests that there is a genetically determined component affecting exercise-related phenotypes. However, since these traits are complex and multifactorial in nature, the search for genes and mutations responsible for the genetic regulation must target not only several families of phenotypes, but also the phenotypes in response to exercise training. It is also obvious that the research on molecular genetics of exercise-related phenotypes is still in its infancy.

The latest update of the human gene map for physical performance and health-related phenotypes included 165 autosomal and 5 X chromosome gene entries and quantitative trait loci (QTLs) (29). Moreover, there were 17 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes. These findings were reported in 270 peer-reviewed research articles (Table 1). A total of 31 genes from 46 studies have been investigated in relation to exercise training-induced changes in hemodynamic (11 genes, 15 studies), body composition (15 genes, 19 studies), plasma lipid and lipoprotein (seven genes, 10 studies), and hemostatic (three genes, three studies) phenotypes. In addition, 29 autosomal genes and three genes encoded by mitochondrial DNA were reported at least in one study to be associated with physical performance-related phenotypes: 18 autosomal and three mitochondrial genes were associated with endurance phenotypes, whereas 14 genes (all autosomal) were associated with speed and muscle strength-related traits (29). As a point of reference, the latest update of a gene map for obesity-related phenotypes included >600 loci (30).

Table 1.

Number of research articles and genetic loci summarized in the 2005 update of the Human Gene Map for Performance and Health-Related Fitness Phenotypes^a

Phenotypes	# of papers	# of loci
Endurance	53	37
Strength and anaerobic	23	20
Hemodynamics	44	48
Body composition	37	34
Insulin and glucoce	16	25
Lipids, inflammation, hemostatic	32	21
Chronic diseases	7	7
Excercise intolerance	52	31
Physical activity	6	14

^aSee ref.29 for details.

The majority of the genes summarized in the human fitness gene map are based on only one study with positive findings. For example, the genes associated with body composition, plasma lipid, and hemostatic phenotype training responses were all based on a single study. However, with hemodynamic phenotypes, some candidate gene findings have been replicated in at least two studies. For example, an association between blood pressure training response and the angiotensinogen (AGT) M235T polymorphism has been reported in both the HERITAGE Family Study and the DNASCO study (31,32). In white HERITAGE males, the AGT M235M homozygotes showed the greatest reduction in submaximal exercise DBP following a 20-week endurance training program (31), whereas in middle-aged Eastern Finnish men, the M235M homozygotes had the most favorable changes in resting SBP and DBP during a 6-year exercise intervention trial (32).

Similarly, an association between the angiotensin-converting enzyme (ACE) I/D polymorphism and training-induced left ventricular (LV) growth has been reported in two studies (Figure 3) (33,34). In 1997, Montgomery and co-workers reported that the ACE D-allele is associated with greater increases in LV mass, and septal and posterior wall thickness after 10 weeks of physical training in British Army recruits (34). In 2001, the same group reported that the training-induced increase in LV mass in another cohort of Army recruits was 2.7 times greater in the D/D genotype as compared to the I/I homozygotes. Interestingly, the association between the ACE genotype and LV mass response was not affected by angiotensin II type 1 receptor inhibitor treatment (33).

Figure 3.

Associations between the angiotensin-converting enzyme (ACE) I/D polymorphism and exercise training-induced increases in left ventricular mass. The left panel shows data from 140 healthy army recruits who participated in a 10-week basic training program (34). Right panel summarizes data from a replication study using a similar training program with 141 healthy recruits (33).

Associations between the angiotensin-converting enzyme (ACE) I/D polymorphism and exercise training-induced increases in left ventricular mass. The left panel shows data from 140 healthy army recruits who participated in a 10-week basic training program (34). Right panel summarizes data from a replication study using a similar training program with 141 healthy recruits (33).

A gene encoding alpha-actinin 3 (ACTN3) has become a popular candidate gene for exercise performance traits recently. A C/T transition in codon 577 of the ACTN3 gene replaces an arginine residue (R577) with a premature stop codon (X577) resulting in a nonfunctional gene product. The stop codon variant is quite common in humans, with allele frequencies ranging from 10% in African populations to 50% in whites and Asians. Some studies have reported that frequency of the stop codon allele or homozygosity for the stop codon variant (X577X) are lower in sprint and strength athletes than in general population (35,36). Similarly, in a cohort of 507 Greek school boys, the X577X homozygotes were significantly slower in a 40-m sprint than the homozygotes for the functional allele. However, the ACTN3 R577X genotype was not associated with sprint time in 439 girls of the same study (37).

In 352 young adult white and Asian women, the X577X homozygotes showed lower baseline values but greater increases in dynamic muscle strength after 12 weeks of strength training, while no differences were found in training responses between the genotypes among 247 men (38). However, a strength training study in elderly men and women found exactly the opposite. In women (n = 86), the X577X homozygotes showed significantly higher baseline knee extensor concentric peak power than the heterozygotes and R577R homozygotes, whereas the improvements brought about by resistance training tended to be greater in the R577R homozygotes than in the stop codon homozygotes (39). Thus, data on the associations between the ACTN3 R577X genotype and sprint performance seem to be fairly consistent. However, more studies are needed to clarify if the ACTN3 locus modifies the effects of resistance training on muscle strength.

Future Directions

Although the research on molecular genetics of physical activity, health-related fitness, and health-related outcomes is still in its infancy, and no genes for exercise-related phenotypes have been confirmed at the level recently recommended for genetic association studies (40), we need to recognize early that some alleles at key genes are likely to play an important role in the ability to benefit from regular exercise. The sooner we incorporate this advance in our thinking and move in the direction of fully integrated molecular epidemiology research, the sooner we will be able to understand the true relation between a sedentary lifestyle or poor fitness and the risk of disease. Moving along this path will provide some of the building blocks that are necessary to bring us eventually in the era of individualized, and hopefully more efficacious, public health recommendations and preventive medicine measures.

We now believe that there are compelling reasons to take into account individual differences in responsiveness to regular physical activity and incorporate genetic information in studies designed to understand the relationships between physical activity, health, and disease. However, it is vital that genetic hypotheses be incorporated early on in the planning of such studies.