A new predictive model for insulin-dependent diabetes mellitus susceptibility based on combinations of molecular HLA-DRB1 and HLA-DQB1 pockets

With a view to establishing an accurate evaluation of the genetic predispos ition to insulin-dependent type I diabetes (IDDM), we have built a model ba sed on the characteristics of the relevant pockets of HLA-DR and -DQ molecu les. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 I DDM patients and 2,391 healthy controls. We formulate the hypothesis that s uceptibility to IDDM is not only explained by the absence of Aspartate 57 ( negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 i n pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logi stic regression method. The 4 components (2 loci and 2 pockets) were system atically analysed in the computer model. It was clearly shown that the stru ctural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9D9 non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, confe rring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DQ and P4DQ give the low est risk with a predictive value of 5%. This mod el of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the re spective role of HLA-DR and -DQ molecules as a major component of susceptib ility to IDDM.