Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans

Abstract

A low maximal oxygen consumption (VO2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases VO2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts VO2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous VO2max response. Two independent preintervention RNA expression data sets were generated (n=41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in VO2max ("predictor" genes). The HERITAGE Family Study (n=473) was used for genotyping. We discovered a 29-RNA signature that predicted VO2max training response on a continuous scale; these genes contained approximately 6 new single-nucleotide polymorphisms associated with gains in VO2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., "reciprocal" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in VO2max, corresponding to approximately 50% of the estimated genetic variance for VO2max. In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. VO2max responses to endurance training can be predicted by measuring a approximately 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.

Clinical physiology and sleep: insights from the European Respiratory Society Congress 2017

“…However, in contrast to the lungs, alterations in skeletal muscles are potentially be reversed by exercise training (15). A large fraction of variance in aerobic capacity gained by exercise training is accounted for by 11 single nucleotide polymorphisms (16). Taking into account this information, Rossiter et al hypothesized that the 11 single nucleotide polymorphisms (SNPs) previously associated with responsiveness to training could be associated with low muscle oxidative capacity in COPD (17).…”

Training-induced gene expression plasticity in cardiac function and neural regulation for ultra-trail runners

“…Most experiments have focused on examining the effects of exercise training versus sedentary subjects [3] or in previously sedentary individuals [4]. The training intensity, duration and type have already been related with specific genetic regulation activity [5].…”

Exercise Genomics

“…This development should provide a flurry of new candidate genes for further in-depth investigation. Another important recent development is the use of gene expression profiling as a tool to identify key genes that can subsequently be subjected to genetic exploration [27,28]. All these methodological advances will be helpful in the effort to identify SNPs and genes associated with exercise endophenotypes and traits.…”

“…GWAS small effect sizes have been repeatedly found with disease endpoints such as type 2 diabetes [30, 31], obesity [32,33], hypertension [34], ischemic heart disease [35,36], and for physical traits such as body height [37]. However, there is some indication it may be easier to find genes and variants associated with exercise-related traits as the effect size is larger for some of them [28]. This is not a trivial issue.…”

“…In a recent report, we demonstrated it was possible to identify DNA markers of the VO 2 max response to standardized exercise training programs [28]. We first used skeletal muscle RNA expression profiling to produce a panel of 29 genes whose baseline expression levels (i.e., in the sedentary state) predicted the VO 2 max training response.…”