A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence ofthe aspartic acid in position 57 (Asp57) of the DQ/i chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ,8 chain, but also introduces the possibility that a DQa chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface ofa heterodimer, composed ofa DQa-chain bearing an Arg52 and a DQ# chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ,# Asp57 and DQa Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation. (J. Clin. Invest. 1990. 85:1315-1319.) HLA * insulin-dependent diabetes mellitus * oligonucleotide typing