Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes

Abstract

Objective: Class II alleles define the main HLA effect on type 1 diabetes, but there is an independent effect of certain class I alleles. Class II and class I molecules are differently involved in the initiation and effector phases of the immune response, suggesting that class I alleles would be important determinants in the rate of β-cell destruction. To test this hypothesis we analyzed the role of HLA class I and class II gene polymorphisms in the progression from diabetes-associated autoimmunity to clinical disease.

Research design and methods: The effect of HLA-DR-DQ haplotypes and a panel of class I HLA-A and -B alleles on the progression from autoantibody seroconversion to clinical diabetes was studied in 249 children persistently positive for at least one biochemical diabetes-associated autoantibody in addition to islet cell autoantibody.

Results: The progression to clinical disease was separately analyzed after the appearance of the first and the second persistent biochemical autoantibody using Cox regression. Multivariate analysis demonstrated a significant protective effect of the A*03 allele (odds ratio [OR] 0.61, P = 0.042 after the first and OR 0.55, P = 0.027 after the second autoantibody), whereas the B*39 allele had a promoting effect after seroconversion for the second autoantibody (OR 2.4, P = 0.014). When children with the DR3/DR4 genotype were separately analyzed, HLA-B*39 had a strong effect (OR 6.6, P = 0.004 and OR 7.5, P = 0.007, after the appearance of the first and the second autoantibody, respectively). The protective effect of A*03 was seen only among children without the DR3/DR4 combination.

Conclusions: These results confirm that class I alleles affect the progression of diabetes-associated autoimmunity and demonstrate interactions between class I and class II alleles.

FIG. 1.

The effect of the HLA-B*39 allele on the progression to type 1 diabetes after seroconversion to persistent positivity for ICA and at least one biochemically-characterized autoantibody in children with the HLA-DR3/DR4 combination (A), and children with other class II genotypes (B). HLA-B*39–positive children indicated by solid line and B*39-negative by dashed line. Kaplan-Meier analysis demonstrated a highly significant difference between the B*39 positive (n = 11) and B*39–negative (n = 53) groups among children carrying the DR3/DR4 combination (P = 0.00007, log-rank test), but no difference was seen between the HLA-B*39–positive (n = 17) and –negative (n = 127) children who did not carry the high-risk HLA class II combination (P = 0.768, log-rank test). The panels below the figure show the number of subjects followed at each time point. AAB, autoantibody; T1D, type 1 diabetes.