The Pro12Ala variant at the peroxisome proliferator-activated receptor gamma gene and change in obesity-related traits in the Diabetes Prevention Program.
OBJECTIVE
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
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).
Franks
P W
PW
Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umea University Hospital, Umea, Sweden.
Jablonski
K A
KA
Delahanty
L
L
Hanson
R L
RL
Kahn
S E
SE
Altshuler
D
D
Knowler
W C
WC
Florez
J C
JC
D000328:Adult; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D002839:Chromans / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008019:Life Style; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D010919:Placebos; D011392:Proline / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000077288:Troglitazone
D002839:Chromans; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010919:Placebos; D045162:Thiazolidinediones; D008687:Metformin; D011392:Proline; D000077288:Troglitazone; D000409:Alanine