Role of genetic and non-genetic factors in the etiology of Graves' disease

n spite of the advancements in understanding the pathogenic mechanisms of Graves' disease (GD), its ultimate cause remains elusive. The majority of investigators agree that GD is likely a multifactorial disease, due to a complex interplay of genetic and non-genetic factors that lead to the loss of immune tolerance to thyroid antigens and to the initiation of a sustained autoimmune reaction. Twin and family studies support a role of genetic factors, among which the HLA complex, CD40, CTLA-4, PTPN22, FCRL3, thyroglobulin, and the TSH receptor may be involved. Among non-genetic factors, iodine, infections, psychological stress, gender, smoking, thyroid damage, vitamin D, selenium, immune modulating agents, and periods of immune reconstitution may contribute the development of the diseases. Here we review in detail the respective role of genetic and non-genetic factors in the etiology of GD, taking advantage of the great bulk of data generated especially over the past 30 years.