Читать книгу Graves' Orbitopathy - Группа авторов - Страница 77

Among the non-modifiable risk factors for GO, male gender and age are significant, although more so for the severity of the disease than for its mere occurrence [65].

Genetic predisposition to GD is demonstrated by familial clustering and twin studies. However, as far as GO is concerned, no clear familial aggregation was observed in 114 consecutive patients with severe GO. Only 3/114 had a family history of GO, and all 3 were second-degree relatives [66].

GD appears to be inherited as a complex multigenic disorder and candidate gene studies (HLA on chromosome 6p21, CTLA4 on chromosome 2q33, LYP on chromosome 1p13 and TSHR on chromosome 14) are promising. The CTLA4 gene is associated with susceptibility to GO. The G allele at exon 1 CTLA4(50)A/G polymorphism is associated with GO (odds ratio 1.65). More importantly, G allele frequency is correlated with severity of GO. The T allele at intron 1 CTLA4(1822)C/T, but not the CTLA4(–318)C/T polymorphism in the promoter region, has also shown an association with GO (odds ratio 1.70). Moreover, exon 1 and intron 1 polymorphisms are in linkage disequilibrium with each other [67]. These findings are in line with the fact that, as for several other autoimmune disorders, the exon polymorphism of CTLA4 is associated with more severe forms. Concerning TSHR, recent work using single-nucleotide polymorphisms has identified an association of the TSHR region with GD, but not autoimmune thyroiditis. However, no data concerning GO were reported in this work [68], and the genes implicated in GO are generally assumed to be the same as for GH. Thyroid peroxidase gene polymorphism has been recently associated with serum levels of thyroid peroxidase antibody in 2 independent genome-wide association studies, and a strong association between the rs11675434 single-nucleotide polymorphism located near thyroid peroxidase and the presence of clinically evident GO has been observed, especially in males [69].

A recent meta-analysis of genetic association studies of interleukin-related genes has shown that among the 8 genes studied, single-nucleotide polymorphisms in IL-1α but not in IL-1β, IL-1RA, IL-4, IL-6, IL-12β, IL-23, and IL-23R were significantly associated with GO; IL-1α is likely to be a genetic biomarker of GO [70]. Polymorphisms in the IL23-R are associated with GO [71]. IL-23, a cytokine more usually associated with innate than adaptive immunity, is secreted in response to infection, especially viral infection [72], and also synergizes with TGF-β to generate the Th17 lymphocyte subset from Th0 precursors, which emphasizes the possible importance of innate immune responses in GD and GO.