Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men.

Aims/hypothesis: The variant allele of the Gly482Ser polymorphism in peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A or PGC1alpha), a critical determinant of skeletal muscle metabolism, has been associated with obesity and type 2 diabetes. Previous studies indicate that these risks depend on sex and environmental triggers such as age. The aim of the present study was to investigate the possible interactions between genotype and age and physical activity on risk of obesity.
Methods: We genotyped PPARGC1A Gly482Ser, in a population-based study comprising 899 women and 902 men aged between 30 and 75 years in Vara, Sweden.
Results: Genotyping revealed that 56% of the males and 57% of the females carried the PPARGC1A 482Ser variant allele. Elderly males (>or=50 years) carrying 482Ser had an increased risk of obesity compared with subjects who were homozygous for the wild-type allele (odds ratio [OR]=1.99, 95% CI 1.14-3.47, p=0.015). The risk was restricted to males with a low leisure-time physical activity level, and was significantly weaker (OR=0.44, 95% CI 0.22-0.87, p=0.018) for the homozygous 482Gly carriers among this subgroup. No association with obesity was found in elderly males with a high level of physical activity, in younger males, or in females of any age group or level of physical activity.
Conclusions/interpretation: Our findings confirm that sex and age should be considered when investigating the influence of the PPARGC1A Gly482Ser polymorphism on metabolic disease. The risk of obesity associated with 482Ser is evident only in physically inactive elderly male subjects. Whenever possible, the level of physical activity should be addressed in future studies on disease risk associated with PPARGC1A Gly482Ser.