Association of HLA-DRB1 pocket structures with susceptibility and prognosis of Graves’ and Hashimoto’s disease

The physical and/or electrical properties of the peptide-binding pockets of Human Leukocyte Antigen (HLA) class II molecules vary depending on their amino acid sequence, influencing peptide-binding affinity. Previous studies have reported associations between HLA-DRB1 amino acid polymorphisms and susceptibility to Graves' disease (GD) and Hashimoto's disease (HD). We hypothesized that polymorphisms in the peptide-binding region of HLA-DRB1 contribute to disease development and prognosis. This study investigated associations between HLA-DRB1 amino acid polymorphisms and both the development and prognosis of autoimmune thyroid diseases. We analyzed HLA-DRB1 sequences in 136 GD patients, 132 HD patients, and 109 healthy Japanese controls. HLA-DRB1 typing was performed using polymerase chain reaction (PCR) with sequence-specific primers (PCR-SSP) and PCR with sequence-based typing (PCR-SBT). Glu9, His13, and Leu67 were more frequent in intractable GD than in GD remission or controls. Lys9, Phe13, Tyr26, and Val57 were associated with susceptibility to HD, whereas Trp9, Ser37, Phe47, and Asp57 were associated with resistance to HD. Structural modeling revealed that GD-susceptible pockets showed a positive electrostatic potential in pocket 7, while GD-resistant pockets showed a negative electrostatic potential. In pockets 4, 7, and 9, HD-susceptible pockets showed a positive electrostatic potential, whereas HD-resistant pockets showed neutral or negative electrostatic potential. Therefore, specific amino acids in pockets 4, 7, and 9 of HLA-DRB1 are associated with the development and prognosis of GD and HD in the Japanese population.