Aims: The T1DGC repository includes sera from ~1500 T1D individuals collected within 3 yrs of onset when autoantibodies to ZnT8 (ZnT8A) persist. The goal of this study was to investigate the genetic associations between ZnT8A, other T1D biomarkers, and biomarkers of other autoimmune disease in these sera.
Methods: ZnT8A and ATP4A were assayed with RIAs using dimeric probes reflecting the major C-terminal epitope variants of ZnT8 (R/W325, R/R325, W/W325) or a derivative probe of ATP4A. The relationship of ZnT8A variants to age, age of diabetes onset, duration of diabetes, gender, and HLA, INS, and CTLA4 alleles was examined using logistic regression. A multinomial regression model was used in association analyses of the number of islet autoantibodies.
Results: ZnT8A were detected in 57% of T1D subjects with the highest frequencies associated with the shortest duration of disease. ZnT8A were prevalent among non-Hispanic whites and blacks, and Hispanics at similar frequencies but significantly less in Asians. The DRB1*0401-DQ8 and DRB1*0404-DQ8 haplotypes were both associated with subjects triple positive for ZnT8A, GADA, and IA2A, but differed for the individual autoantigens with the DRB1*0404-DQ8 haplotype associated with ZnT8A+ sera. A negative association with HLA-A24 was also observed.
Conclusions: Both the frequency and titer of ZnT8A declined with increased duration of T1D consistent with previous studies particularly for sera binding to both R/R325 and W/W325 probes (unrestricted). Moreover, an apparent duration-dependent increase in frequency of R/W325 bindingsera implies these epitopes may be preferentially preserved. Our data suggest a positive association with HLA-DQ6.4 not indicated for GADA or IA2-A. The HLA-A*24, associated with rapid progression to T1D, was shown to be negatively associated with ZnT8A as previously reported. Our results are consistent with previously reported HLA associations. Our novel results show differential effects of DR4-DQ8 haplotypes and possible negative associations with DQ5, DQ7.5 and DQ6.2.