ASSOCIATION OF HLA-A24 WITH COMPLETE BETA-CELL DESTRUCTION IN IDDM

A sensitive C-peptide immunoreactivity radioimmunoassay demonstrated t he presence of subtle, but definite residual beta-cell function in pat ients with IDDM of long duration. Although HLA antigens are known to i nfluence susceptibility to IDDM, their contribution to the extent of p ancreatic beta-cell destruction has not yet been examined extensively. We studied the relationship between residual beta-cell function and H LA class I and class II antigens in 111 unrelated Japanese IDDM patien ts. Using the sensitive C-peptide immunoreactivity radioimmunoassay, t he presence or absence of residual beta-cell function was evaluated by the C-peptide immunoreactivity response to a 100-g oral glucose load. DNA typing for HLA-DQA1 and HLA-DQB1 antigens was performed in additi on to serological typing of HLA-A, HLA-B, HLA-C, and HLA-DR antigens. A C-peptide immunoreactivity response >0.033 nM was regarded as an ind ication of the presence of residual beta-cell function, not the assay error. Surprisingly, 35 of 37 (94.6%) patients without residual beta-c ell function had HLA-A24, whereas only 39 of 74 (52.7%) patients with residual beta-cell function had this antigen (corrected P = 9.795 x 10 (-6)). Any other HLA antigens, including the DR and DO loci, showed no difference in the frequency with regard to residual beta-cell functio n. The duration of diabetes was similar between the groups with and wi thout residual beta-cell function. Even when the patients were stratif ied according to the duration of diabetes, HLA-A24 was more common in those with early complete loss of beta-cell function (duration of diab etes < 1 yr) (P = 0.035) and was less common in those with residual be ta-cell function despite a long duration of diabetes (> 10 yr) (P = 0. 001). The correlation between HLA-A24 positivity and complete beta-cel l loss also was confirmed in younger-onset (< 30 yr old) and elder-ons et (greater-than-or-equal-to 30 yr old) groups. The C-peptide immunore activity response in patients with HLA-A24 (0.09 +/- 0.02 nM, mean +/- SE, n = 74) was significantly lower than that in patients without HLA -A24 (0.19 +/- 0.03 nM, n = 37, P < 5.0 x 10(-5)). Further typing of H LA-A24 by one-dimensional isoelectric focusing gel electrophoresis rev ealed that the isoelectric point of HLA-A24 was identical in charge in 17 of 18 patients and 7 normal control subjects (isoeletric point 6.3 2, HLA-A24.1). We conclude that a specific HLA class I antigen, HLA-A2 4, promotes pancreatic beta-cell destruction in IDDM patients with oth er disease-susceptible HLA antigens.