Interaction of DIO2 T92A and PPARgamma2 P12A polymorphisms in the modulation of metabolic syndrome.
Type 2 iodothyronine deiodinase (DIO2) converts thyroid prohormone tetraiodothyronine into the biologically active triiodothyronine hormone, which increases insulin sensitivity at the skeletal muscle level. The DIO2 T92A polymorphism modulates deiodinase activity and has been inconsistently associated with insulin resistance. Also, the P121A polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene, which encodes a transcription factor involved in insulin signaling, has been inconsistently associated with insulin resistance. This study was aimed at evaluating the combined effect of DIO2 T92A and PPARgamma2 P12A polymorphisms on insulin resistance-related features in 590 non-diabetic whites. A significant gene-gene interaction was observed in the modulation of systolic (p = 0.01) and diastolic (p = 0.02) blood pressure and metabolic syndrome (p = 0.02), with carriers of both DIO2 A92 and PPARgamma2 A12 variants showing the worst phenotype. This latter interaction was also shown by multifactor dimensionality reduction analysis (p = 0.0045). A peroxisome proliferator response element in the DIO2 promoter was identified by in silico analysis and confirmed by in vitro gel shift mobility assay, thus providing a biological plausibility for the observed gene-gene interaction. If confirmed in other populations, comprising several thousand individuals, these data may help identify individuals at risk for insulin resistance-related abnormalities.
Fiorito
Mirella
M
CSS-Mendel Institute, viale Regina Margherita, 261, 00198 Roma, Italy.
Torrente
Isabella
I
De Cosmo
Salvatore
S
Guida
Valentina
V
Colosimo
Alessia
A
Prudente
Sabrina
S
Flex
Elisabetta
E
Menghini
Rossella
R
Miccoli
Roberto
R
Penno
Giuseppe
G
Pellegrini
Fabio
F
Tassi
Vittorio
V
Federici
Massimo
M
Trischitta
Vincenzo
V
Dallapiccola
Bruno
B
D000328:Adult; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics*; D007558:Italy; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D047495:PPAR gamma; D000097564:Iodothyronine Deiodinase Type II