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1 European University of Madrid, Madrid, Spain
2 Department of Toxicology, Complutense University, Madrid, Spain
3 Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge, Cambs, United Kingdom
4 Department of Sports Medicine, Higher Sports Council, Madrid, Spain
5 School of Nursing, Complutense University, Madrid, Spain
6 MRC Epidemiology Unit, Cambridge, Cambs, United Kingdom
7 The Cooper Institute Center for Human Performance and Nutrition Research, Dallas, TX, USA
8 Phoenix Epidemiology & Clinical Research Branch, NIDDK-NIH, Phoenix, AZ, USA
* To whom correspondence should be addressed. E-mail: pfranks{at}niddk.nih.gov.
Animal and human data indicate a role for the peroxisome proliferator-activated receptor-
coactivator 1
(PPARGC1A) gene product in the development of maximal oxygen uptake (VO2max), a determinant of endurance capacity, diabetes, and early death. We tested the hypothesis that the frequency of the minor Ser482 allele at the PPARGC1A locus is lower in World-class Spanish male endurance athletes (cases) (n=104; mean [SD] age: 26.8 [3.8] y) than in unfit UK Caucasian male controls (n=100; mean [SD] age: 49.3
[8.1] y). In cases and controls, the Gly482Ser genotype met Hardy-Weinberg expectations (p>0.05 in both groups tested separately). Cases had significantly higher
VO2max (73.4 [5.7] vs. 29.4 [3.8] ml.kg-1.min-1; p<0.0001) and were leaner (BMI: 20.6 [1.5] vs. 27.6 [3.9] kg/m2; p<0.0001) than controls. In unadjusted 
2 analyses, the frequency of the minor Ser482 allele was significantly lower in cases than in controls (29.1 vs. 40.0%; p=0.01). To assess the possibility that genetic stratification could
confound these observations, we also compared Gly482Ser genotype frequencies in Spanish (N=164) and UK Caucasian males (N=381) who were unselected for their level
of fitness. In these analyses, Ser482 allele frequencies were very similar (36.9% in Spanish vs. 37.5% in UK Caucasians, p=0.83), suggesting that confounding by genetic
stratification is unlikely to explain the association between Gly482Ser genotype and endurance capacity. In summary, our data indicate a role for the Gly482Ser genotype in determining aerobic fitness. This finding has relevance from the perspective of physical performance, but may also be informative for the targeted prevention of diseases associated with low fitness such as type 2 diabetes.
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