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Evidence That HLA Class I and II Associations With Type 1 Diabetes, Autoantibodies to GAD and Autoantibodies to IA-2, Are Distinct

OBJECTIVE A major feature of type 1 diabetes is the appearance of islet autoantibodies before diagnosis. However, although the genetics of type 1 diabetes is advanced, the genetics of islet autoantibodies needs further investigation. The primary susceptibility loci in type 1 diabetes, the HLA class I and II genes, are believed to determine the specificity and magnitude of the autoimmune response to islet antigens. We investigated the association of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA-2A) with the HLA region. RESEARCH DESIGN AND METHODS Associations of GADA and IA-2A with HLA-DRB1, HLA-DQB1, HLA-B, HLA-C, HLA-A, MICA, and 3,779 single nucleotide polymorphisms (SNPs) were analyzed in 2,531 childhood-onset case subjects (median time since diagnosis 5 years). All analyses were adjusted for age-at-diagnosis and duration of diabetes. RESULTS GADA and IA-2A were associated with an older age-at-diagnosis (P < 10−19). For GADA, the primary association was with HLA-DQB1 (P = 9.00 × 10−18), with evidence of a second independent effect in the HLA class I region with SNP, rs9266722 (P = 2.84 × 10−6). HLA-DRB1 had the strongest association with IA-2A (P = 1.94 × 10−41), with HLA-A*24 adding to the association, albeit negatively (P = 1.21 × 10−10). There was no evidence of association of either IA-2A or GADA with the highly type 1 diabetes predisposing genotype, HLA-DRB1*03/04. CONCLUSIONS Despite genetic association of type 1 diabetes and the islet autoantibodies localizing to the same HLA class II genes, HLA-DRB1 and HLA-DQB1, the effects of the class II alleles and genotypes involved are quite different. Therefore, the presence of autoantibodies is unlikely to be causal, and their role in pathogenesis remains to be established.

as dependent variable and genotype (or allele) as independent variable was used to test for association with type 1 diabetes. Note, geographical region was included as a confounder to account for variation in disease incidence and allele/genotype frequency across Great Britain (refer to methods of main text). A genotype effects model (which does not assume a specific mode of inheritance) was compared to a multiplicative allelic effects model. The multiplicative model, as is well known, was not an appropriate approximation (P < 7 x 10 -20 ) (10; 11).

Effects of duration of diabetes on genetic associations with autoantibody positivity
As most cases were tested for autoantibodies after diagnosis, autoantibody positivity would be less than had all cases been tested for autoantibodies at time of diagnosis; we estimate the false negative rate to be less than 20%. This effect of duration on autoantibody positivity has been accounted for in the statistical analysis by including duration as a covariate in the regression models. Here we illustrate this with reference to the HLA-DRB1*03/04 genotype.
First consider whether or not HLA-DRB1*03/04 is associated with GADA positivity. This can be tested in a logistic regression model, using GADA positivity as the outcome variable and HLA-DRB1*03/04 genotype as independent variable. However, GADA is associated with increasing age-at-diagnosis, and HLA-DRB1*03/04 is also associated with age-at-diagnosis, i.e. age-at-diagnosis is a confounder to be included in the model. GADA positivity has a sex bias (more females are GADA positive than males) so sex is included as a covariate. Using a likelihood ratio test, this model (GADA ~ age-at-diagnosis + sex + DR3/4) could be compared to a model without DR3/4, to determine whether or not DR3/4 is associated with GADA positivity. However, with this test, association of genotype with decline in GADA positivity with diabetes duration, could be detected but interpreted as association of GADA positivity with HLA-DRB1*03/04 genotype. Therefore, to account for decline in GADA positivity with diabetes duration, duration was included as a covariate. No evidence of association of GADA positivity with HLA-DRB1*03/04 genotype was obtained, P = 0.33. As the duration variable was included, decline in autoantibody positivity with disease duration was not tested.
Association of the HLA-DRB1*03/04 genotype with decline in GADA positivity with increasing duration of disease can be tested. We do not have the appropriate study design for this and so the study (across individuals) does not have much statistical power to detect this, but we can apply the test. Using an interaction term in the logistic regression model with GADA positivity as the outcome variable, the independent variables are then HLA-DRB1*03/04 genotype, age-at-diagnosis, sex, duration of disease, and the interaction of HLA-DRB1*03/04 with duration. This interaction term allows us to test the genotype dependence of decline in GADA positivity with duration of disease by comparing this model to a model without the interaction term using a likelihood ratio test. This was not significant, P = 0.15. So there was no association of genotype with decline in GADA positivity in our cohort with a median disease duration of 5 years.
Note however, whether or not there is a genotype dependence of decline in autoantibody positivity with duration of disease a priori is unknown, so for all tests the duration variable was included to ensure we are testing association of GADA positivity with genotype without being confounded by decline in GADA positivity with diabetes duration.
Using the same methods, there was no evidence of a HLA-DRB1*03/04 genotype dependence on decline in IA-2A positivity with duration of diabetes, P = 0.08. Furthermore, HLA-DRB1*03/04 was not associated with IA-2A positivity P=0.92.      HLA-B haplotypes. The haplotypes listed without an OR were grouped together and labeled "Rares" as they were individually too rare to estimate effects in the regression model. ORs are reported using the most common haplotype as reference (HLA-B*X.HLA-DRB1*04) and also using the neutral rare haplotypes as reference. 48] X denotes, any allele other than HLA-B*18, *08 or *39 at HLA-B and any allele other than HLA-DRB1*04, HLA-DRB1*03 or HLA-DRB1*01 at HLA-DRB1.