The Pro12Ala and C-681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren

Aims/hypothesis: Peroxisome proliferator-activated receptor gamma is an important regulator of adiposity in mouse and man, and common variation in the PPARG gene has been associated with birthweight, adult obesity, insulin sensitivity and type 2 diabetes. We hypothesised that these variants may be associated with childhood obesity. Methods: Height and weight were recorded for 2454 prepubertal children aged between 4 and 10 years, who were then genotyped for three common variants of the PPARG locus: C-681G, Pro12Ala and C1431T. Results: No single variant of PPARG was significantly associated with height, weight or BMI. However, when modelling the variants together we detected an opposing interaction between the -681G and the Ala12 variants in height and weight, but not BMI (p=0.018, 0.013 and 0.119 respectively). The data were consistent with the Ala12 carriers being deficient in energy storage/utilisation, leading to reduced growth. In contrast, the -681G variant, which has been associated with increased adult height, was associated with accelerated growth. The two variants were in strong linkage disequilibrium. However, rare individuals bearing the isolated variants demonstrated the greatest variation from the mean, the most contrasting genotypes being associated with a variation of 7 kg in weight and 6 cm in height, standardised to 7.4-year-olds (p=0.006 and p=0.02 respectively). Conclusion/Intepretations: This study demonstrates that quantitative trait analysis of energy balance/growth and the PPARG locus is complex and requires the use of multiple genetic markers.