A key issue of Really Significant Genes (RSG) that caused Graves Disease is unresolved. RSGs are considered likely major contributors to genetic risk for a disease. These genes should be strongly linked within families and they could become clinically useful as predictors of disease. Some Graves Disease susceptibility genes have been identified. The first identified was the Human-Leucocyte-Antigen DR (HLA-DR) gene locus, then a non-HLA genes as cytotoxic T lymphocyte antigen (CTLA-4), CD40, protein tyrosine phosphatase-22 (PTPN22), thyroglobulin, and thyroid-stimulating hormone receptor (TSHR) gene. The sites observed in different populations were not always the same. With the completion of the HapMap, which provided the geography of thousands single nucleotide polymorphisms (SNPs), the search of more minor associated genes started again although studies never revealed stronger candidates, meanwhile, the role of the environment in disease development remains poorly understood. The importance of the environment with the mechanisms involved including genetic factors is needed to be decided.
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