The Pro12Ala variant at the peroxisome proliferator-activated receptor gamma gene and change in obesity-related traits in the Diabetes Prevention Program

Abstract

Aims/hypothesis: Peroxisome proliferator-activated receptor gamma (PPARgamma), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA.

Methods: We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n = 989), troglitazone (n = 363) or lifestyle modification (n = 1,004) vs placebo (n = 1,000) for diabetes prevention in high-risk individuals.

Results: At baseline, Ala12 carriers had larger waists (p < 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p = 0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p = 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p = 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p < 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p = 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p < or = 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p = 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p = 0.04) was also observed, which was most evident with metformin treatment (p < 0.001).

Conclusions/interpretation: Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992).

Figures

Fig. 1

Association between the Pro12Ala genotype and weight change (kg) at 1 year stratified by treatment group. White bars, Pro12Pro genotype carriers; black bars, data from Ala12X genotype carriers. Data are adjusted means and 95% CI. The p values are for the tests of difference for change in weight by genotype (Pro12Pro vs Ala12X), within treatment groups. The test of interaction between genotype and treatment groups was statistically significant (p=0.01)

Fig. 2

Association between Pro12Ala genotype and 1 year change in CT-assessed abdominal fat areas SAT lumbar 2/3 (a), SAT lumbar 4/5 (b), VAT lumbar 2/3 (c) and VAT lumbar 4/5 (d) stratified by treatment group. White bars, data from Pro12Pro genotype carriers; black bars, data from Ala12X genotype carriers. Data are adjusted means and 95% CIs. The p values are for the tests of difference for change in adipose mass by genotype (Pro12Pro vs Ala12X), within treatment groups. The test of interaction between genotype and treatment groups was not statistically significant for any CT measure

Fig. 3

Interaction between Pro12Ala genotype and polyunsaturated to saturated dietary fatty acid ratio (P:S ratio) for CT-assessed abdominal fat areas SAT lumbar 2/3 (a), SAT lumbar 4/5 (b), VAT lumbar 2/3 (c) and VAT lumbar 4/5 (d) in individuals randomised to metformin treatment. White bars, data from Pro12Pro genotype carriers (n=198); black bars, data from Ala12X genotype carriers (n=51). Data are adjusted means and 95% CIs. p= 0.125 (a), p=0.626 (b), p=0.064 (c) and p=0.0003 (d) for the tests of interaction between genotype (Pro12Pro vs Ala12X) and P:S ratio as a continuous trait, as reported in the Results