Lack of an independent association between the human leukocyte antigen allele DQA1*0501 and Graves' disease

The association between the human leukocyte antigen (HLA) serotype DR3 and Graves' disease (GD) in Caucasian populations is well known. However, an even stronger association has been reported recently, especially in the male population, between the closely linked HLA allele DQA1*0501 and GD. We postulated that the reported association between DQA1*0501 and GD may be a result of the linkage of this allele with DR3 and may not represent an independent association. Accordingly, we screened a population of North American Caucasians (n = 218), including patients with GD (n = 101, 32 males, 69 females) and individuals with documented normal thyroid function (n = 117, 51 males, 66 females), for the presence of the DQA1*0501 allele and those alleles corresponding to the DR3 serotype (DRB1*03). Screening was accomplished using sequence specific PCR. A significant association was documented in the total study population between DR3 positivity and GD (P = 0.0002), but not between DQA1*0501 positivity and GD (P = 0.06). After gender stratification, significant associations were found only in the female population (DR3, P = 0.0004; DQA1*0501, P = 0.012) and not in the male population(DR3, P = 1.0; DQA1*0501, P = 1.0).Additionally, in those DR3 negative female subjects (n = 100), there was no independent association between DQA1*0501 positivity (n = 26) and GD (p = 0.82). P-values were corrected, where appropriate, for gender stratification and/or the number of HLA alleles tested. In conclusion, our results demonstrate a lack of independent association between the presence of the HLA allele DQA1*0501 and GD. We suggest that the apparent association between this allele and GD in the female population may be the result of its' close linkage to DR3.