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

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.