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

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.

Paediatric‐onset and adult‐onset Graves' disease share multiple genetic risk factors

“…A total of 1267 patients with a confirmed diagnosis of GD, including 179 paediatric‐onset GD patients (age of GD onset ≤18 years; POGD) and 1088 unrelated adult‐onset GD patients (age of GD onset >18 years; AOGD), were enrolled to the study. This group comprised four independent Polish‐Caucasian cohorts consecutively recruited at four tertiary care medical centres in Warsaw, Gliwice, Wroclaw and Bialystok; all cohorts have been precisely described in the previous studies . Criteria for the diagnosis of GD were the same in all patients, including clinical and biochemical symptoms of hyperthyroidism accompanied by diffuse goitre, detectable TSH receptor autoantibodies and/or increased radioiodine uptake, as previously described .…”

“…This group comprised four independent Polish-Caucasian cohorts consecutively recruited at four tertiary care medical centres in Warsaw, Gliwice, Wroclaw and Bialystok; all cohorts have been precisely described in the previous studies. 14,[27][28][29] Criteria for the diagnosis of GD were the same in all patients, including clinical and biochemical symptoms of hyperthyroidism accompanied by diffuse goitre, detectable TSH receptor autoantibodies and/or increased radioiodine uptake, as previously described. 14,[27][28][29] The control group comprised a total of 1054 healthy subjects (285 males and 769 females) recruited at the participating institutions; this group also included cohorts used in the previous studies.…”

“…14,[27][28][29] Criteria for the diagnosis of GD were the same in all patients, including clinical and biochemical symptoms of hyperthyroidism accompanied by diffuse goitre, detectable TSH receptor autoantibodies and/or increased radioiodine uptake, as previously described. 14,[27][28][29] The control group comprised a total of 1054 healthy subjects (285 males and 769 females) recruited at the participating institutions; this group also included cohorts used in the previous studies. 14,[27][28][29] All patients and controls gave their written informed consent to participate in the study.…”

In Vivo Effects of Retrobulbar Bimatoprost Injection on Orbital Fat

“…16 Further evidence for the importance of PPARγ in TED is supported by the observation that a polymorphism that downregulates the PPARγ gene may be protective against developing the manifestations of TED. 17 This may explain why patients without TED who are exposed to a PPARγ agonist such as thiazolidinedione agents may experience fat-predominant proptosis. 10,13,14 …”

Quantitative PPARγ expression affects the balance between tolerance and immunity

“…For example, the most common PPARG polymorphism, Pro12Ala, which exhibits decreased transcriptional activity41, is associated with several autoimmune diseases such as psoriatic arthritis42 and rheumatoid arthritis43. However, the polymorphism is also associated with delayed onset of multiple sclerosis44 and with protection against Graves orbitopathy45. Another common PPARG polymorphism, C161T, was associated with the longer survival of Japanese patients with IgA nephropathy46.…”