Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-gamma 2 (PPAR-gamma 2): divergent modulating effects on body mass index in obese and lean Caucasian men

Aims/hypothesis. The objectives of the present investigation were to examin e: 1) whether a Pro115Gln variant in the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) is associated with juvenile-onset obesity a mong Danish Caucasianmen and 2) whether the relation of a Pro12Ala polymorp hism in PPAR-gamma 2 with BMI and long-term weight regulation differ betwee n lean and obese subjects within the same cohort. Methods. The Pro115Gln and Pro112Aln variants were examined using PCR and R FLP in a group of 752 subjects with a Body Mass Index (BMI) of 31.0 kg/m(2) or more and in 869 non-obese control subjects. Results. We did not find Pr o115Gln in any of the 1621 male subjects we examined. Among the males with juvenile-onset obesity, the allelic frequency of the Pro12Ala polymorphism was 14% (95% confidence interval: 12-16%) compared with 16% (14-17%) among the non-obese control subjects (NS). Heterozygosity of the codon 12 variant was not associated with differences in BMI or changes in body weight regul ation during follow up in lean or obese subjects. In the group of obese sub jects, 21 homozygous Ala12Ala carriers had, however, a higher BMI (38.9 +/- 5.4 kg/m(2) (means +/- SD) vs 35.5 +/- 5.5 kg/m(2), p = 0.008) and a highe r weight gain (0.27 +/- 0.24 kg.m(-2).year(-1) vs 0.10 +/- 0.24 kg.m(-2).ye ar(-1), p = 0.004), compared with wild-type carriers. Moreover, within the control group of 869 men the 14 homozygous carriers of the variant had a lo wer BMI (24.4 +/- 2.7 kg/m(2) vs 26.2 +/- 3.7 kg/m(2), p = 0.005) and a slo wer increase in BMI (0.11 +/- 0.11 kg.m(-2).year(-1) vs 0.17 +/- 0.11 kg.m( -2).year(-1), p = 0.002) compared with wild-type carriers. Conclusion/interpretation. The codon 12 variant of PPAR-gamma 2 is not intr insically associated with juvenile obesity. The variant may in its homozygo us form interact, however, with various combinations of genetic and environ mental factors in lean and obese subjects to cause divergent modulating eff ects on BMI and long-term body weight control.