Marissa Honda's List: EXSC Group Project

• Research focused on exercise at the genetic or genomic level has typically involved investigations of genes that affect quantitative measures known to be directly influenced by exercise (e.g., muscle mass, bone density, and so forth) or investigations of disease outcomes that are influenced by both genetic effects and exercise (e.g., hypertension in exercising and nonexercising individuals). A limited number of researchers have investigated the genetic basis of exercise or activity level as a phenotype itself. Gottschaldt (13) studied the concordance, or similarity, of various mental and physical activity traits in monozygotic twins over the span of 30 yr and found that, although cognitive skills remained highly concordant throughout a lifetime, the physical activity level did not, suggesting that environmental factors rather than genetic factors are more important in determining an individual's propensity to be active in adulthood. Although the genetic basis of activity level has not been as well studied as personality traits and thinking skills, other researchers have reported similar findings (38). Family studies have provided heritability estimates for physical activity, measured by self-report or by observation, ranging from 0.29 to 0.62, with the wide range in estimates likely due to differences in the age and type of the subject samples as well as in the physical activity assessment instruments (22, 37). No gene has yet been identified for physical activity level, although genes related to metabolic rate might predispose an individual to be active or inactive.
• Exercise can also affect health status indirectly by altering the expression or action of one or more genes that influence intermediate phenotypes (e.g., cholesterol level) that ultimately produce disease outcomes.
• Genome or chromosomal scans have been conducted for metabolic rate (35), bone density (34), body fat measures (36), insulin (19), blood pressure (24, 25, 45), O_{2 max} (9), and other metabolic intermediates. However, a functional gene/variant has yet to be elucidated within candidate gene regions identified by these studies. One explanation for the lack of findings may be that detection of the effects of any one polymorphism on a complex trait, such as metabolic rate, for example, may be dependent on the context in which the variant is being analyzed (e.g., exercisers vs. nonexercisers). That more systematic attention has not been focused on the study of gene-environment interaction probably reflects the difficulties involved in conducting such studies in humans: large samples are needed, multiple polymorphisms must be typed in all subjects, demographic and environmental variables must be measured, and complex analytic methods are required. The primary limiting factor in genetic analyses stratified by activity level or other environmental factors is sample size, as even moderately large samples (e.g., 1,000 individuals) may have strata that contain only a handful of subjects. Nevertheless, studies of gene-environment interaction are critical if we are to make the most efficacious use of genetic information to improve overall health.

  • VO2 max is difficult to measure
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• Bouchard and colleagues (39, 40) investigated several polymorphisms in the genes for enzymes that regulate energy metabolism and cellular ion exchange and reported a significant association between a variant in the muscle-specific creatine kinase gene and O_{2 max} and significant associations between polymorphisms present in the Na-K-ATPase 2 and 1 genes and resting heart rate, resting and exercise blood pressure, and rate pressure product. These examples illustrate that selection of candidate genes based on physiological pathways has proved to be a useful strategy to detect genes that are modified by exercise.

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• Led by Dr. Soren Snitker at the University of Maryland and his postdoctoral fellow, Evadnie Rampersaud, who is now at the University of Miami, the team studied 704 Amish men and women.

  • take into account the fact they're Amish
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• Within the Amish study group, some volunteers had two copies of a fattening variant; these people were 67% more likely to be obese and were on average 7 lbs. heavier than people without any copies of this form of the gene.
• But researchers also discovered a subgroup of volunteers who had two copies of the heavy FTO variant, but still managed to avoid being fat. Their simple trick? Exercise. Rampersaud found that the most physically active men and women in the study were able to stay within a normal BMI range, despite their genetic predisposition; other people with the same gene variants, who were relatively inactive, were overweight.

  • Is it possible that the people who have "fat gene" but aren't fat have a genetically higher VO2 max (endurance to exercise)?
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• Notes Dr. David Katz, director of the Yale-Griffin Prevention Research Center, the current study, which was published in the Archives of Internal Medicine, highlights a critical new understanding in the relationship between genes and our lifestyle. It's long been known that we can compensate for our genetic makeup by our lifestyle choices — by watching what we eat and how much we exercise, for example — but as this study shows, it's now becoming clear that our lifestyle patterns may actually alter our genes and the way they are expressed as well. "We can nurture nature," he says, "and the idea that you can alter genetics through lifestyle is an emerging theme. The power of lifestyle is dramatic."

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• That’s one of the conclusions of research published by the American College of Sports Medicine (ACSM.) As presented in the November issue of ACSM’s official journal, Medicine & Science in Sports & Exercise®, the study updates the human gene map for fitness and physical performance.
• “Some people are gifted,” said lead researcher Claude Bouchard, Ph.D., FACSM, referring to such characteristics as cardiorespiratory endurance, strength, flexibility, and body composition. Genetics play a big role in such matters, as they do in “trainability” - the capacity to benefit from exercise. “But,” said Bouchard, “there’s no correspondence between the genes responsible for your being advantaged, even as a sedentary person and those allowing you to gain from exercise.”

  • says no correspondence between genes that make you BETTER at exercising and genes that make YOU gain better results
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• beyond physical traits, there are significant genetic differences in people’s inclination to be physically active. Likewise, different people may achieve different results from the same activity.
• “We’re beginning to see a new area emerge: studies focusing on the role of genetic differences in the inclination to be physically active. Recently, studies have investigated specific genes for their potential contribution to physical activity or the propensity to be sedentary. That’s new-that’s an important line of research.”
• “We haven’t been able to influence people’s behavior to change dramatically their level of physical activity or sedentarism,” said Bouchard. “Compared with the magnitude of the problem, we’ve made very small progress. I contend that there are biological forces that force us back into the same groove when we change from being sedentary to being more active. Those forces are partly determined by our genetic makeup. Thus, research into genetic factors underlying exercise and physical activity levels is a very worthwhile area to pursue from a public health perspective.”
  

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• the researchers specifically looked at what is called VO2 max, or aerobic capacity.
• Bottom line, VO2 max represents your endurance. And this study, detailed today in the Journal of Applied Physiology, suggests a group of 29 genes could potentially categorize individuals into low, medium and high responders to exercise.
• So-called low responders "may not see an improvement in their tolerance to exercise, or any improvement in their capacity to do the exercise, but their blood levels of cholesterol and lipids may improve quite substantially,"

  • Bray refers to this as "altering intermediate phenotypes." Referring to how exercise can alter genes
• said lead researcher Claude Bouchard, of the Pennington Biomedical Research Center in Baton Rouge, La.

• However, about 20 years ago, some scientists started to question whether or not the link between training and fitness level was so clearcut. For instance, in the so-called Heritage family study, Bouchard and colleagues had about 500 relatively sedentary individuals train for 20 weeks between 1992 and 1997. Participants' ability to improve their fitness varied greatly lot, despite the fact that all participants rigorously adhered to the same exercise regime.
• Genes could account for about half of the difference they were seeing in people's ability to increase their VO2 max.
• Of this 50 percent, the newly identified genes can only explain about 23 percent of the variation in an individual's ability to be trained to improve VO2 max.
• In addition, in the Heritage study, the people who improved their fitness (VO2 max) the most weren't necessarily the ones who improved their blood pressure the most, or lowered their cholesterol.
• So these factors, which are thought to be indicators for heart disease risk, could be controlled by different genes, Bouchard said.
• if someone learns they are a "low responder" to exercise, they know they may need to be more aggressive with their training in order to see an increase in their endurance.

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