PURPOSE: To evaluate the association of human leukocyte antigen (HLA) types in Japanese patients with Graves ophthalmopathy.

METHODS: Japanese patients with severe ophthalmopathy (48 patients) and patients without ophthalmopathy (46 patients) were selected prospectively from 234 consecutive patients with hyperthyroid Graves disease. The criteria for severe ophthalmopathy were proptosis of 19 mm or more, or a 3-mm difference in exophthalmometry measurement between the two eyes, or diplopia at the primary eye position. The criteria for the absence of ophthalmopathy were proptosis of 16 mm or less, no diplopia, no lid retraction, and no thickening of extraocular muscles. Serologic HLA typing of class I and II antigens was performed in the two patient groups. The frequency of each HLA antigen in the two patient groups was compared to that in 767 unrelated normal healthy Japanese controls.

RESULTS: The frequencies of HLA-DR14 and DQ1 were significantly higher in the patient group with severe ophthalmopathy (35% and 75%, respectively) than in healthy controls (4% and 43%, respectively; corrected P < .05), and also greater than in the patient group without ophthalmopathy (13% and 55%, respectively; P < .01). On the other hand, the frequencies of HLA-B35, B54, DR4, and DQ4 were significantly higher in the patient group without ophthalmopathy (23%, 23%, 43%, and 30%, respectively) than in the patient group with severe ophthalmopathy (13%, 15%, 25%, and 19%, respectively; P < .01).

CONCLUSIONS: HLA-DR14 and DQ1 antigens may be genetic markers of predisposition to the development of severe ophthalmopathy. In addition, HLA-B35, B54, DR4, and DQ4 may be genetic markers of resistance to severe ophthalmopathy. Variation in the severity of ophthalmopathy associated with Graves disease may depend, in part, on the presence or absence of particular HLA antigens.