Susceptibility genes in Graves' ophthalmopathy: searching for a needle in a haystack?

The variety of clinical presentations of eye changes in patients with Graves' disease suggests that complex interactions between genetic, environmental, endogenous and local factors influence the development/severity of Graves' ophthalmopathy (GO). At present, the role of genetic factors in the development of GO remains unknown. Based on small case-control association studies with candidate genes, several susceptibility loci in GO have been proposed. These are human leucocyte antigen (HLA, 6p21.3), cytotoxic T-lymphocyte antigen-4 (CTLA-4, 2q33), tumour necrosis factor (TNF, 6p21.3), interferon-gamma (IFN-gamma, 12q14), intercellular adhesion molecule-1 (ICAM-1, 19p13), and thyroid stimulating hormone receptor gene (TSH-R, 14q31). Unfortunately, these results were either not confirmed or require replication in larger studies. There are many reasons for the lack of reproducibility of association studies in GO, including poor characterization of the studied groups and small sample sizes, which may result in both false positive and negative results. Thus, the genetic background of GO remains to be elucidated in future research. However, the possibility that GO may be a genetically heterogeneous disorder, or that the development of GO may be predominantly influenced by environmental factors such as cigarette smoking, can not be disregarded.