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.
Highlights
A statistical technique that relies on the principle that genes act in a coordinated manner, and not in isolation, found an upregulation in the oxidative phosphorylation (OXPHOS) gene set (FDR ϭ 1.1%), consistent with the increased lipid oxidation profile
Despite the use of baseline physiological data to personalize the clinical intervention in all three studies, ϳ20% of subjects demonstrated Ͻ5% improvement in maximal aerobic capacity
If we consider the strong relationships between aerobic capacity and morbidity and mortality, the approach defined in this study has the potential to provide insight into the role of regular exercise and its molecular determinants in metabolic control of glucose and lipid metabolism, blood pressure regulation, and inflammation in humans
Summary
Enrichment of disease-associated gene networks, generated from RNA expression data, with genotyping data has successfully enhanced the explanatory power of the analysis [13]. We hypothesized that baseline RNA expression profiling would identify genes with relevant genetic variants that relate to the large intersubject trait variation observed in humans. We apply this rationale to study maximal aerobic power and identify and blindly validate a novel gene signature that predicts the magnitude of adaptation to supervised exercise-training programs
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