Endocrine Abstracts

Understanding the genetic etiology of Graves’ disease (GD) and Graves’ orbitopathy (GO) is recognized as an urgent priority. Since peroxisome proliferator-activated receptors α (PPARα) exhibit anti-inflammatory and immunomodulatory activity, and are required for the control of the adipose inflammation process their role in the GD and GO pathogenesis has been proposed. Abnormal expression and/or function of PPARα could suppress the inflammatory response by direct up regulation of gene(s) with anti-inflammatory properties.

Three SNPs within PPARα gene: rs135551 (c.−127+5148A>G), rs1800206 (c.484C>G), (Leu162Val) and rs4253766 (c.712-3784C>T) were investigated in 276 Polish Caucasian GD patients in the context of presence, activity and severity of GO, as well as familial history of thyroid disease, response to the anti-thyroid treatment and gender or smoking status. SNPs were determined with use of the allelic discrimination methods.

Although, univariate analysis did not found any association with risk of GO as well as with its activity or severity we found a specific haplotype rs135551(G)/rs1800206(G)/rs4253766(C) which 3.47 times increase the risk of severe GO (χ²=5.10, P=0.02). Moreover the same haplotype was statistically significant more frequent in smokers (OR=7.73, χ²=4.77, P=0.03) as well as 4.17-times increased the risk of severe GO (χ²=6.81, P=0.009) whereas haplotype rs135551(A)/rs1800206(G)/rs4253766(C) significantly decreased the risk of severe eye symptoms (OR=0.013, χ²=4.43, P=0.04). Additionally, univariate analysis showed a trend toward increased frequency of rs135551 (GG) genotype (P=0.06) and (G) allele ((GG) and/or (GC) genotypes) (P=0.08) in smokers. Furthermore, there was also a trend toward increased frequency of rs13551 (A) allele ((AA) and/or (GA) genotypes) and haplotype rs13551(G)/ rs1800206(C)/ rs4253766(C) in responders to anti-thyroid treatment (P=0.07 and P=0.07 respectively). The rs13551 (GG) genotype was statistically significantly increased in patients without familial background (OR=1.75, P=0.04) but haplotype rs13551(A)/ rs1800206(G)/ rs4253766(C) was 106.42 times more frequent in patients with familial history of thyroid disease (χ²=3.65, P=0.05).

Our association study suggests that PPARα polymorphisms may be involved in the pathogenesis of GD and GO.