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FRANKS, P. W., I. BARROSO, J. LUAN, U. EKELUND, V. E. F. CROWLEY, S. BRAGE, M. S. SANDHU, R. W. JAKES, R. P. S. MIDDELBERG, A.-H. HARDING, A. J. SCHAFER, S. O’RAHILLY, and N. J. WAREHAM. PGC-1α Genotype Modifies the Association of Volitional Energy Expenditure with V̇O2max. Med. Sci. Sports Exerc., Vol. 35, No. 12, pp. 1998–2004, 2003. Sedentary lifestyles are increasingly common and result in low cardiorespiratory fitness (V̇O2max), a well-established predictor of early mortality and coronary heart disease (CHD). Adaptation in V̇O2max after exercise training varies considerably between people. Because there are hereditary components to fitness, it is likely that genetic factors explain some of this variability. PPARGC1 (PGC-1α) coactivates genes involved in energy transduction and mitochondrial biogenesis. Transgenic mouse data demonstrate that overexpression of PGC-1α mRNA increases endurance capacity by transformation of nonoxidative to oxidative skeletal muscle tissue. Other murine studies demonstrate that exercise increases PGC-1α mRNA expression.To explore whether a candidate polymorphism in the PGC-1α gene modifies the association between physical activity energy expenditure (PAEE) and predicted V̇O2max (V̇O2max.pred).We examined whether the Gly482Ser polymorphism of PGC-1α modified the relationship between objectively measured PAEE and V̇O2max.pred in a population-based sample of 599 healthy middle-aged people. PAEE was assessed using individual calibration with 4 d of heart rate monitoring. V̇O2max.pred was measured during a submaximal exercise stress test on a bicycle ergometer.Homozygosity at the Ser482 allele was found in 12.7% of the cohort, whereas 38.9% and 48.4% carried the Gly482Gly and Gly482Ser genotypes, respectively. The association between PAEE and V̇O2max.pred (mL·kg−1·min−1) was strongest in people homozygous for the Ser482 allele (β = 12.03; P < 0.00001) compared with carriers of the Gly allele (β = 5.61; P < 0.00001). In a recessive model for the Ser482 allele, the interaction between PAEE and genotype on V̇O2max.pred (L·min−1) was highly significant (P = 0.009).Our results indicate that Ser482 homozygotes may be most capable of improving cardiorespiratory fitness when physically active, and that Gly482Ser may explain some of the between-person variance previously reported in cardiorespiratory adaptation after exercise training.