Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

A negative association between HLA-A*24 and islet autoantibody responses in pre-diabetes (#132)

Jody Ye 1 , Anna Long 2 , Kyla Chandler 1 , Polly Bingley 1 , Alistair Williams 1 , Kathleen Gillespie 1
  1. School of Clinical Sciences, University of Bristol, Bristol
  2. Benaroya Research Institute, Seattle


Individuals with type 1 diabetes (T1D) carrying HLA-A*24, which is associated with rapid progression, have a lower prevalence of autoantibodies to zinc transporter 8 (ZnT8A) and the protein tyrosine phosphatase domains of islet antigen-2 (IA-2A) and IA-2β (IA-2βA), but not to insulin (IAA) or GAD (GADA)1,2,3. We postulated that these immunogenetic associations may provide insights into the natural history of islet autoimmunity. The aim of this study was to examine HLA-A*24 and autoantibody associations in a cohort of individuals at high risk of progression to T1D.

Materials and methods

491 islet cell antibody (ICA) positive at-risk first degree relatives, recruited to the European Nicotinamide Diabetes Intervention Trial (ENDIT) (first Ab+ sample, median age 15.7 yr (IQR 10.5-33.3), median follow-up 5.0 yr (IQR 3.2-5.0)) had HLA-DQ and islet autoantibody profile established by PCR-SSO and radio-immunoassay, respectively. Of these, DNA samples were available on 374 (76%). HLA-A*24 was analysed by PCR-SSP. Autoantibody prevalence and genotype were compared using χ2 testing and logistic regression.


333 participants had additional islet autoantibodies: IAA (n=208); GADA (n=287); ZnT8A (n= 208); IA-2A (n=201); IA-2βA (n=128). There was a negative association between HLA-A*24 and autoantibodies to GAD (41.3% vs. 59.6%, p=0.005), ZnT8 (26.2% vs. 44.3%, p=0.010), and insulin (29.5% vs. 43.6%, p=0.047) but not to IA-2. Logistic regression analysis also demonstrated a negative association between HLA-A*24 and prevalence of antibodies to GAD, insulin and ZnT8 but not IA-2.


In pre-diabetes HLA-A*24 is negatively associated with antibodies to insulin and GAD, while negative associations with ZnT8A and IA-2A are weaker than those observed in “at diagnosis” and “established” diabetes. This suggests a dynamic interaction between genotype and autoantibody responses and may reflect the effects of aggressive HLA class I-mediated CD8 responses in HLA-A*24 positive individuals on islet autoimmunity.

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  2. Howson JM, Krause S, Stevens H, Smyth DJ, Wenzlau JM, Bonifacio E, Hutton J, Ziegler AG, Todd JA, Achenbach P.Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases. Diabetologia 2012; 55:1978-1984
  3. Anna E. Long,Kathleen M. Gillespie,Rachel J. Aitken,Julia C. Goode,Polly J. Bingley and Alistair J.K. Williams. Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes. Diabetes 2013; 62:2067-2071