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

Authors

  • Mirella Fiorito,

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Isabella Torrente,

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Salvatore De Cosmo,

    1. Research Laboratory of Diabetes and Endocrinology, CSS Institute, San Giovanni Rotondo, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Valentina Guida,

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Experimental Medicine and Pathology, Sapienza University, Rome, Italy
    3. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Alessia Colosimo,

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Compared Biomedical Sciences, University of Teramo, Teramo, Italy
    3. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Sabrina Prudente,

    1. CSS-Mendel Institute, Rome, Italy
    2. Research Laboratory of Diabetes and Endocrinology, CSS Institute, San Giovanni Rotondo, Italy
    3. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Elisabetta Flex,

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Experimental Medicine and Pathology, Sapienza University, Rome, Italy
    3. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Rossella Menghini,

    1. Department of Internal Medicine, Tor Vergata University, Rome, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Roberto Miccoli,

    1. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
    2. Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy
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  • Giuseppe Penno,

    1. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
    2. Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy
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  • Fabio Pellegrini,

    1. Research Laboratory of Diabetes and Endocrinology, CSS Institute, San Giovanni Rotondo, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Vittorio Tassi,

    1. Research Laboratory of Diabetes and Endocrinology, CSS Institute, San Giovanni Rotondo, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Massimo Federici,

    1. Department of Internal Medicine, Tor Vergata University, Rome, Italy
    2. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • Vincenzo Trischitta,

    Corresponding author
    1. CSS-Mendel Institute, Rome, Italy
    2. Research Laboratory of Diabetes and Endocrinology, CSS Institute, San Giovanni Rotondo, Italy
    3. Department of Experimental Medicine and Pathology, Sapienza University, Rome, Italy
    4. Department of Clinical Sciences, Sapienza University, Rome, Italy
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  • Bruno Dallapiccola

    1. CSS-Mendel Institute, Rome, Italy
    2. Department of Experimental Medicine and Pathology, Sapienza University, Rome, Italy
    3. Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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  • The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

CSS-Mendel Institute, viale Regina Margherita, 261, 00198 Roma, Italy. E-mail: vincenzo.trischitta@uniroma1.it

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) γ2 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 PPARγ2 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 PPARγ2 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.

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