Strong association between HLA-DQA1*0501 and Graves' disease in a male Caucasian population

Graves' disease (GD) is an autoimmune thyroid disease and is associated with human leukocyte antigen (HLA)-DR3 and -DQA1*0501 in caucasians. The incidence of GD is 5 times higher in females than in males, possibly due to their greater immune reactivity. Although many attempts have been made to correlate HLA phenotypes and clinical features of GD little attention has been paid to possible heterogeneous HLA distribution among patients of different sexes. To investigate this possibility, 133 (26 males) unrelated caucasian patients with GD and 104 (43 males) control subjects were typed for HLA-DRB1, -DQA1, and -DQB1, using sequence-specific oligonucleotide probes to analyze polymerase chain reaction-amplified DNA. There were no significant differences in HLA distribution between male and female controls. The frequencies of HLA-DQA1*0501 were increased in both [88.5%; relative risk (RR) = 9.13; P = 0.000015] and female patients (66.4%; RR = 2.66; P = 0.00046) compared to that in the entire control group (42.3%). The frequencies of DR11 (RR = 2.83; P = 0.019) and DQB1*0301 (RR = 2.50; P = 0.034) were increased only in male patients, whereas that of DR3 was higher in female (RR = 2.39; P = 0.0066) and male (RR = 2.54; not significant, P = 0.051) patients, suggesting the possible heterogeneous HLA distribution between the sexes. When the male and female patients were compared, a significant difference was found only for DQA1*0501. The prevalence of DQA1*0501 was significantly higher in males than in females (P = 0.019). As females have augmented immune responsiveness, we speculate that considerable numbers of females may develop GD without a strong HLA susceptibility allele, whereas only a few males develop GD without it.