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PPARg2 Ala12 variant protects against Graves' orbitopathy and modulates the course of the disease

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Abstract

Orbital fibroblast differentiation to adipocytes is a peroxisome proliferator-activated receptor g (PPARg)-dependent process essential for pathogenic tissue remodeling in Graves' orbitopathy (GO). PPARg2 Pro12Ala polymorphism modulates expression and/or function of the molecule encoded by this gene and is a promising locus of GO. Here, we analyzed associations of PPARg2 Pro12Ala with clinical manifestation of GO in 742 Polish Caucasians including 276 Graves' disease (GD) patients. In our study, the Ala12 allele and Ala12 variant (Ala12Ala and/or Pro12Ala genotype) decreased the risk of GO (p = 0.000012 and p = 0.00013). Moreover, Ala12Ala genotype was observed only in patients without GO (p = 0.002). GD patients with Ala12 variant had less active and less severe eye symptoms. Female carriers of the Ala12 allele rarely developed GO, but the marker was not related to symptoms of GO. The opposite finding was recorded in males, in whom the studied polymorphism was related to activity, but not to the development, of GO. In Ala12 variant carriers without familial history of thyroid disease, risk of GO was lower than in persons with a familial background. The Ala12 allele seemed to protect smokers from GO, but in nonsmokers, such a relation was not obvious. A multivariate analysis indicated the Pro12Ala marker as an independent risk factor of eye symptoms (p = 0.0001) and lack of Ala increases the risk of GO 3.24-fold. In conclusion, the gain-of-function Ala12 variant protects against GO and modulates the course of the disease.

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Acknowledgments

This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Experimental Therapy, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114, Wroclaw, Poland

    Edyta Pawlak-Adamska & Irena Frydecka

  2. Department of Endocrinology, Diabetes, and Isotope Therapy, Medical University, Pasteura 4, 50-367, Wroclaw, Poland

    Jacek Daroszewski, Marek Bolanowski & Przemyslaw Janusz

  3. Department of Ophthalmology, Medical University, Pasteura 4, 50-367, Wroclaw, Poland

    Jolanta Oficjalska

  4. Department of Ophthalmology, Medical University, Borowska 213, 50-556, Wroclaw, Poland

    Marek Szalinski

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  1. Edyta Pawlak-Adamska
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  2. Jacek Daroszewski
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Correspondence to Edyta Pawlak-Adamska.

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Pawlak-Adamska Edyta and Daroszewski Jacek equally contributed to this paper.

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Pawlak-Adamska, E., Daroszewski, J., Bolanowski, M. et al. PPARg2 Ala12 variant protects against Graves' orbitopathy and modulates the course of the disease. Immunogenetics 65, 493–500 (2013). https://doi.org/10.1007/s00251-013-0702-0

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