PPARGC1Agenotype (Gly482Ser) predicts exceptional endurance capacity in European men

Abstract

Animal and human data indicate a role for the peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PPARGC1A) gene product in the development of maximal oxygen uptake (V(O2 max)), 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) yr] than in unfit United Kingdom (UK) Caucasian male controls [n = 100; mean (SD) age: 49.3 (8.1) yr]. In cases and controls, the Gly482Ser genotype met Hardy-Weinberg expectations (P > 0.05 in both groups tested separately). Cases had significantly higher V(O2 max) [73.4 (5.7) vs. 29.4 ml x kg(-1) x min(-1) (3.8); P < 0.0001] and were leaner [body mass index: 20.6 (1.5) vs. 27.6 kg/m2 (3.9); P < 0.0001] than controls. In unadjusted chi2 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 men (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 it may also be informative for the targeted prevention of diseases associated with low fitness such as Type 2 diabetes.

PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene × environment interactions in children from the European Youth Heart Study

“…The most widely studied PPARGC1A variant is the Gly482Ser non-synonymous polymorphism. Since the initial report of association between this variant and type 2 diabetes [2], many others have reported statistical associations with diabetes-related traits [3,5,7,9,10]. Here we observed a nominal statistical association between Gly482Ser and waist circumference, but no associations were observed for other traits.…”

“…Associations between Gly482Ser and type 2 diabetes [2,3], hypertension [4], obesity [5], dyslipidaemia [6][7][8], aerobic fitness [9] and insulin resistance [10] have been widely reported. However, a thorough exploration of common PPARGC1A variants and their associations with metabolic or cardiovascular disease traits is yet to be reported in adults or children.…”

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

“…Other possible explanations for the heterogeneity observed are gene-gene and geneenvironment interactions such that the effect of the Gly482Ser polymorphism is different in different populations. Indeed, evidence for gene-environment interaction at this gene has been demonstrated [23][24][25]. Geneenvironment interactions may lower the power to detect true associations when performing cross-sectional studies, including meta-analysis of cross-sectional studies, such as in this study.…”

PGC1α gene Gly482Ser polymorphism predicts improved metabolic, inflammatory and vascular outcomes following bariatric surgery

“…8 However, there are studies suggesting a neutral or protective role for this polymorphism in obesity, metabolic and cardiovascular diseases. [11][12][13] Thus, further work is required to provide a more in-depth view of the role of this polymorphism in human health and disease.…”