Interaction of DIO2 T92A and PPARγ2 P12A Polymorphisms in the Modulation of Metabolic Syndrome

Abstract

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) ␥2 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 PPAR␥2 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 ϭ 0.01) and diastolic (p ϭ 0.02) blood pressure and metabolic syndrome (p ϭ 0.02), with carriers of both DIO2 A92 and PPAR␥2 A12 variants showing the worst phenotype. This latter interaction was also shown by multifactor dimensionality reduction analysis (p ϭ 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.

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

“…The D2-Thr92Ala polymorphism was associated with higher risk for arterial hypertension in 372 euthyroid subjects not on thyroid hormone replacement therapy (31). The only other positive association between this variant and blood pressure was reported by Fiorito et al (60). Patients who are carriers of both the minor variant of D2-Thr92Ala and PPARg2-Pro12Ala polymorphism had significantly higher diastolic and systolic blood pressures.…”

“…Deiodinase polymorphisms may affect intracellular thyroid hormone concentration and thereby lipoprotein metabolism. The effect of the Thr92Ala polymorphism on serum lipid parameters was evaluated in various diabetic and non-diabetic cohorts (5, 32,38,58,59,60,61). No associations between HDL, LDL, total cholesterol, or triglyceride levels and genotype status were found in any of the reports studying this relationship.…”

“…HOMA-IR) yielded several nonsignificant reports (31,32,60,61,64). Of note, a small number of DM2 patients (4.2%) were included in the study of Grarup et al (61).…”

“…The isolated effect of the D2-Thr92Ala polymorphism demonstrated no significant effect on BMI in a variety of studies in which this potential association was investigated (5, 28,29,32,34,60,61,63). In 960 non-diabetic Caucasians, carriers of both a variant (Trp64Arg) located in the b3-adrenergic receptor (ADRB3) and the minor allele of the D2-Thr92Ala variant displayed an increased BMI (4).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Moreover, the possibility of a functional linkage of the Thr92ALA polymorphism with Pro121Ala in PPARγ2 needs to be considered, since the combination of the two SNPs can modulate insulin-resistance, hypertension and other features of metabolic syndrome (126).…”