Evidence for interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms in determining type 2 diabetes intermediate phenotypes in overweight subjects.
BACKGROUND
The peroxisome proliferator-activated receptor-gamma ( PPARG) Pro12Ala and the PPARG co-activator-1alpha ( PPARGC1A) Gly482Ser polymorphisms (SNPs) have been associated with type 2 diabetes mellitus (T2DM) risk. We hypothesized that independent and interactive effects of the PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms influence T2DM intermediate phenotypes.


METHODS
PPARG Pro12Ala and PPARGC1A Gly482Ser SNPs were studied in 680 non diabetic subjects who underwent a 75 g oral glucose tolerant test (OGTT). Glucose and insulin plasma levels in the fasting state and derived from the OGTT were included in the present study.


RESULTS
We found significant independent effects of the PPARG and PPARGC1A variants on fasting insulin levels (p=0.02 for both), HOMA-IR (p=0.03 and p=0.02, respectively), insulin area under the curve (AUC) (p=0.007 and p=0.006, respectively) and 2-h glucose levels (p=0.02 for PPARGC1A). Furthermore, significant gene-gene interactions were found for fasting insulin, HOMA-IR and insulin AUC (p=0.03 for all). Carriers of the PPARGC1A Gly allele who were also PPARG Ala-carriers had higher fasting insulin levels (p=0.02), HOMA-IR (p=0.01) and insulin AUC (p=0.01) compared to the Ser/Ser-Ala+genotype combination, whereas no differences between the PPARGC1A genotypes among the PPARG Pro/Pro carriers were observed.


CONCLUSIONS
Together, these results showed that PPARG Pro12Ala and PPARGC1A Gly482Ser variants are associated, alone and in interaction, with insulin and glucose homeostasis and suggest that gene-gene interactions should be taken into account in candidate gene studies of T2DM to identify subjects with markedly different risks of developing the disease.
Ruchat
S-M
SM
Department of Preventive Medicine, Laval University, Quebec, Canada.
Weisnagel
S J
SJ
Vohl
M-C
MC
Rankinen
T
T
Bouchard
C
C
Pérusse
L
L
D000328:Adult; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005951:Glucose Tolerance Test; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D001786:Blood Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors