Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans.
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.
Panum Institutet and Center for Healthy Ageing, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Jamie.timmons@gmail.com
James A
JA
Timmons
Steen
S
Knudsen
Tuomo
T
Rankinen
Lauren G
LG
Koch
Mark
M
Sarzynski
Thomas
T
Jensen
Pernille
P
Keller
Camilla
C
Scheele
Niels B J
NB
Vollaard
Søren
S
Nielsen
Thorbjörn
T
Akerström
Ormond A
OA
MacDougald
Eva
E
Jansson
Paul L
PL
Greenhaff
Mark A
MA
Tarnopolsky
Luc J C
LJ
van Loon
Bente K
BK
Pedersen
Carl Johan
CJ
Sundberg
Claes
C
Wahlestedt
Steven L
SL
Britton
Claude
C
Bouchard
D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics*; D010641:Phenotype; D010807:Physical Endurance / Q000235:genetics*; D005082:Physical Exertion / Q000502:physiology*; D010809:Physical Fitness / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
D009124:Muscle Proteins