Limited genetic susceptibility to severe Graves' ophthalmopathy: No role for CTLA-4 but evidence for an environmental etiology

Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (o rbitopathy), which presents with varying degrees of severity. Graves' disea se clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear, We have studied the family his tory of 114 consecutive, ethnically mixed patients with severe Graves' opht halmopathy (GO). Patients were selected by unambiguous single ascertainment . Seventy-seven percent of patients were female and 59% smoked. The mean ag e at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-de gree relative affected with either Graves' disease (GD) or Hashimoto's thyr oiditis (HT). The segregation ratio for AITD in nuclear families in our asc ertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only) . Hence, the higher prevalence of AITD among relatives of Graves' ophthalmo pathy patients agreed with the known genetic predisposition to AITD and thi s predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all sec ond-degree relatives) and the segregation ratio for GO was 0. These data di d not support a major role for familial factors in the development of sever e Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for as sociation with Graves' ophthalmopathy. These were negative except for the H LA and CTLA-4 genes, which were found to be weakly associated with GO givin g similar relative risk (RR) as in GD patients without ophthalmopathy. Thes e data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophtha lmopathy. Smoking remains one example of such potential external insults.