POLYMORPHIC AMINO-ACID VARIATIONS IN HLA-DQ ARE ASSOCIATED WITH SYSTEMATIC PHYSICAL PROPERTY CHANGES AND OCCURRENCE OF IDDM

The association between human leukocyte antigen (HLA) and insulin-depe ndent diabetes was studied in a large population-based investigation u sing genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects, As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA10301, DQ A10501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protectio n, Combining Asp-57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did no t explain susceptibility or protection either, DQA10301-DQB1*0302 (DQ 8) and DQA10301-DQB1*0301 (DQ7) are identical except for four amino a cid substitutions in the beta-chain, but DQ8 was positively (odds rati o 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) ass ociated with the disease, Molecular modeling was used to determine whe ther physicochemical properties such as steric factors and surface ele ctrostatic potentials also differ in a systematic way for various DQ m olecules, Amino acids were substituted systematically at the four poly morphic sites, and the solvent-accessible surfaces and electrostatic p otentials were computed for each molecule, Dramatic alterations in ele ctrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1, The variation of physicochemical proper ties due to polymorphic substitutions may be significant to the mechan ism of HLA-DQ association with insulin-dependent diabetes, via the eff ect these property variations have on peptide antigen binding selectiv ity and subsequent interactions with specific T-cell receptors.