POLYMORPHISMS OF TAP1 AND TAP2 GENES IN GRAVES-DISEASE

Graves' disease is an autoimmune disorder in which HLA DQA10501 and D QB10201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding r egions and display only a limited degree of polymorphism. Since polymo rphisms of TAP might influence susceptibility to Graves' disease by a possibly different selection of antigenic peptides, we investigated se quence variants of TAP1 and TAP2 genes in 235 patients with Graves' di sease and 218 random healthy controls by polymerase chain reaction (PC R) followed by sequence specific oligonucleotide analysis (SSO), singl e strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP10301 (Val-333/Asp-637: 71% vs . 55% in controls, p<0.008, RR=2.05) and TAP20101 (Val-379/Ala-565/Th r-665/stop-687: 83% vs. 69% in controls, p<0.03, RR=2.20) showed a pos itive association with Graves' disease whereas TAP10401 a negative (I le-333/Gly-637: 4% vs. 13% in controls, p<0.01, RR=0.25). After select ion of patients and controls for HLA DQA10501 a similar association w as found for TAP10301 (72% vs. 50% in controls, p<0.02, RR=2.63) and TAP10401 (4% vs. 16% in controls, p<0.04, RR=0.22), when matching for HLA DQB10201 as well as for TAP1*0401 (3% vs. 16% in controls, p<0.0 5, RR=0.18). Our findings indicate that the positive association of TA P10301 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.