Advances in Exercise, Fitness, Performance Genomics in 2011
Advances in Exercise, Fitness, Performance Genomics in 2011
In 2011, several peer-reviewed articles were published on endurance performance, mainly in elite athletes. Most of these studies (e.g., Ash et al., Chiu et al., Maciejewska et al., and Mikami et al.) were based on a case-control design and were characterized by the same limitations that we highlighted last year and that were further addressed in a recent publication. Although some studies had replication data, the small sample size and the lack of clearly defined physiological phenotypes were consistent limiting factors. Three recently published articles were based on innovative study designs and/or unique analytic strategies with relatively large sample sizes; we are reviewing them below.
The first article by Keller et al. used a combination of transcriptomics and genomics to describe the effect of endurance training on skeletal muscle phenotypes. In a prior publication by the same group, approximately 800 skeletal muscle gene transcripts were shown to be up- or downregulated by 6 wk of endurance training in sedentary subjects. These transcripts were identified as the trainingresponsive transcriptome (TRT). In the more recent publication, the same group studied the potential regulatory molecules coordinating the complex network of exercisetraining regulated genes using different cohorts, including 24 sedentary and healthy men who performed 6 wk of endurance training. In addition, genotyping was performed on 473 white subjects from the HERITAGE Family Study cohort, and a novel outbred rodent aerobic capacity model was studied. All three approaches were combined in an attempt to develop a more complete picture of the genetic basis of endurance performance traits.
The TRT was examined by contrasting subjects who were low or high responders to exercise training. At least 100 of the 800 TRT genes were differentially regulated between the two groups, suggesting they may be critical for the improvement of aerobic capacity. Subsequently, from a panel of 3400 single nucleotide polymorphisms (SNPs) in the HERITAGE study cohort, several DNA variants showed associations with the trainability of maximal aerobic power. However, after the conservative Bonferroni correction, none of the SNPs remained statistically significant. In the rat model, selected from 10 generations of high responders to aerobic training, there was evidence to the effect that in these animals, the TRT and a subset of the human high-responder genes were regulated to a greater degree in the high-responder rodents. These complex but internally consistent data were taken as evidence for a powerful gene expression program that characterizes successful adaptation to aerobic training. Interestingly, the transcripts involved belong mainly to development-, tumor biology–, and immunology-related pathways. From a clinical point of view, it will be interesting to see whether these findings, describing a gene-based responder status to regular exercise programs, will be replicated and eventually provide us with the foundation to individualize exercise programs in a preventive or therapeutic context.
A second new report based on a GWAS undertaken with more than 320,000 SNPs on the sample of whites in HERITAGE was recently published. The first finding was that a total of 39 individual SNPs were associated with V̇O2max training response at P < 1.5 × 10, with none of the associations reaching the genome-wide significance level of 5 × 10. The strongest evidence of association (P = 1.3 × 10) was observed with an SNP located in the first intron of the acyl-CoA synthetase long-chain family member 1 (ACSL1) gene. Subsequently, when all 39 SNPs were analyzed simultaneously in multivariate regression models, nine SNPs each accounted for at least 2% (range = 2.2% to 7.0%) of the variance (P < 0.0001 for all), whereas seven other SNPs each contributed between 1% and 2%. Collectively, these 16 SNPs accounted for 45% of the variance in V̇O2max trainability. It turns out that this is a value comparable to the heritability estimate of 47% reported previously in HERITAGE.
Finally, a genomic predisposition score was constructed with the 21 SNPs that were entered in the final regression model, and each SNP was coded on the basis of the number of high–V̇O2max training response alleles: the low-response allele homozygotes were assigned 0, heterozygotes received 1, and homozygotes for the high-response allele were coded as 2. Thus, the theoretical range of the genomic predisposition score was from 0 (no beneficial alleles) to 42 (two copies of the beneficial alleles at all 21 loci). The data show that the observed scores ranged from 7 to 31. Importantly, the magnitude of the difference in V̇O2max training response between those with the lowest (9 or less, n = 36, mean = +221 mL·min) and the highest (19 or more, n = 52, mean = +604 mL·min) genomic predisposition scores was 383 mL·min. These observations strongly suggest that it will eventually be possible to predict in sedentary adults the magnitude of the V̇O2max training response to be expected using a panel of genomic markers.
The third interesting publication came out of the CAREGENE cohort, which comprises 935 CAD patients who completed a 3-month ambulatory supervised exercise training program with two to three (average = 2.27) 90-min training sessions per week. Before and after the training program, patients completed a maximal graded exercise test on a cycle ergometer with respiratory gas analysis. Thomaes et al. investigated a set of 21 SNPs in 12 muscle-related genes in the CAREGENE subjects. A genetic predisposition score was calculated, and its predictive value was tested. In summary, they found suggestive associations for the changes in aerobic capacity with single SNPs in the ciliary neurotrophic factor (CNTF), the AMP deaminase 1 (AMPD1), and the glucocorticoid receptor (GR, now known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) genes. In addition, the genetic predisposition score was a significant predictor of whether a patient belonged to the responder or the nonresponder V̇O2max gain group as a result of the training regimen. This publication and the previous one from HERITAGE emphasize that a predisposition score offers new opportunities to optimize the prediction of trainability and may have practical value in the future as suggested earlier.
In summary, the three publications reviewed herein represent a trend toward more powerful experimental studies with innovative designs and larger sample sizes. As suggested in our review of last year, the combination of transcriptomics and genomics seems to be particularly useful for the investigation of the genetic regulation of endurance performance phenotypes.
Endurance Performance
In 2011, several peer-reviewed articles were published on endurance performance, mainly in elite athletes. Most of these studies (e.g., Ash et al., Chiu et al., Maciejewska et al., and Mikami et al.) were based on a case-control design and were characterized by the same limitations that we highlighted last year and that were further addressed in a recent publication. Although some studies had replication data, the small sample size and the lack of clearly defined physiological phenotypes were consistent limiting factors. Three recently published articles were based on innovative study designs and/or unique analytic strategies with relatively large sample sizes; we are reviewing them below.
The first article by Keller et al. used a combination of transcriptomics and genomics to describe the effect of endurance training on skeletal muscle phenotypes. In a prior publication by the same group, approximately 800 skeletal muscle gene transcripts were shown to be up- or downregulated by 6 wk of endurance training in sedentary subjects. These transcripts were identified as the trainingresponsive transcriptome (TRT). In the more recent publication, the same group studied the potential regulatory molecules coordinating the complex network of exercisetraining regulated genes using different cohorts, including 24 sedentary and healthy men who performed 6 wk of endurance training. In addition, genotyping was performed on 473 white subjects from the HERITAGE Family Study cohort, and a novel outbred rodent aerobic capacity model was studied. All three approaches were combined in an attempt to develop a more complete picture of the genetic basis of endurance performance traits.
The TRT was examined by contrasting subjects who were low or high responders to exercise training. At least 100 of the 800 TRT genes were differentially regulated between the two groups, suggesting they may be critical for the improvement of aerobic capacity. Subsequently, from a panel of 3400 single nucleotide polymorphisms (SNPs) in the HERITAGE study cohort, several DNA variants showed associations with the trainability of maximal aerobic power. However, after the conservative Bonferroni correction, none of the SNPs remained statistically significant. In the rat model, selected from 10 generations of high responders to aerobic training, there was evidence to the effect that in these animals, the TRT and a subset of the human high-responder genes were regulated to a greater degree in the high-responder rodents. These complex but internally consistent data were taken as evidence for a powerful gene expression program that characterizes successful adaptation to aerobic training. Interestingly, the transcripts involved belong mainly to development-, tumor biology–, and immunology-related pathways. From a clinical point of view, it will be interesting to see whether these findings, describing a gene-based responder status to regular exercise programs, will be replicated and eventually provide us with the foundation to individualize exercise programs in a preventive or therapeutic context.
A second new report based on a GWAS undertaken with more than 320,000 SNPs on the sample of whites in HERITAGE was recently published. The first finding was that a total of 39 individual SNPs were associated with V̇O2max training response at P < 1.5 × 10, with none of the associations reaching the genome-wide significance level of 5 × 10. The strongest evidence of association (P = 1.3 × 10) was observed with an SNP located in the first intron of the acyl-CoA synthetase long-chain family member 1 (ACSL1) gene. Subsequently, when all 39 SNPs were analyzed simultaneously in multivariate regression models, nine SNPs each accounted for at least 2% (range = 2.2% to 7.0%) of the variance (P < 0.0001 for all), whereas seven other SNPs each contributed between 1% and 2%. Collectively, these 16 SNPs accounted for 45% of the variance in V̇O2max trainability. It turns out that this is a value comparable to the heritability estimate of 47% reported previously in HERITAGE.
Finally, a genomic predisposition score was constructed with the 21 SNPs that were entered in the final regression model, and each SNP was coded on the basis of the number of high–V̇O2max training response alleles: the low-response allele homozygotes were assigned 0, heterozygotes received 1, and homozygotes for the high-response allele were coded as 2. Thus, the theoretical range of the genomic predisposition score was from 0 (no beneficial alleles) to 42 (two copies of the beneficial alleles at all 21 loci). The data show that the observed scores ranged from 7 to 31. Importantly, the magnitude of the difference in V̇O2max training response between those with the lowest (9 or less, n = 36, mean = +221 mL·min) and the highest (19 or more, n = 52, mean = +604 mL·min) genomic predisposition scores was 383 mL·min. These observations strongly suggest that it will eventually be possible to predict in sedentary adults the magnitude of the V̇O2max training response to be expected using a panel of genomic markers.
The third interesting publication came out of the CAREGENE cohort, which comprises 935 CAD patients who completed a 3-month ambulatory supervised exercise training program with two to three (average = 2.27) 90-min training sessions per week. Before and after the training program, patients completed a maximal graded exercise test on a cycle ergometer with respiratory gas analysis. Thomaes et al. investigated a set of 21 SNPs in 12 muscle-related genes in the CAREGENE subjects. A genetic predisposition score was calculated, and its predictive value was tested. In summary, they found suggestive associations for the changes in aerobic capacity with single SNPs in the ciliary neurotrophic factor (CNTF), the AMP deaminase 1 (AMPD1), and the glucocorticoid receptor (GR, now known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) genes. In addition, the genetic predisposition score was a significant predictor of whether a patient belonged to the responder or the nonresponder V̇O2max gain group as a result of the training regimen. This publication and the previous one from HERITAGE emphasize that a predisposition score offers new opportunities to optimize the prediction of trainability and may have practical value in the future as suggested earlier.
In summary, the three publications reviewed herein represent a trend toward more powerful experimental studies with innovative designs and larger sample sizes. As suggested in our review of last year, the combination of transcriptomics and genomics seems to be particularly useful for the investigation of the genetic regulation of endurance performance phenotypes.
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