Polymorphisms of TAP1 and TAP2 genes in Graves' disease.

Graves' disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' disease as additional permissive and protective factors.