Genetic association of zinc transporter 8 (ZnT8) Autoantibodies in type 1 diabetes Cases

Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Diabetologia (Impact Factor: 6.67). 04/2012; 55(7):1978-84. DOI: 10.1007/s00125-012-2540-2
Source: PubMed


Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.
The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes.
Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific.
ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.

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    • "The ‘ZnT8Ab’-component was associated with a genetic fingerprint based on SNPs closest to TAF5L, HNF1B, CDKAL1 and ERBB3 genes, which are all expressed in β-cells ( No studies have found this combined genetic association with ZnT8Abs [37], but there are studies relating TAF5L [38] and ERBB3 [39] to T1D and CDKAL1 [40] and HNF1B [41] to T2D. We did not find the SLC30A8 gene to be present in the genetic pattern of the ‘ZnT8Ab’-component, although we know there is a very strong correlation between the rs1326634 SNP of the SLC30A8 gene and the subtype of ZnT8Ab, such that the CC genotype carriers have higher ZnT8Arg and vice versa [6], [8]. "
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    • "We showed that this negative association was reflected in the level of the IA-2A response and was largely explained by reduced reactivity to epitopes in the PTP regions of IA-2 and IA-2β. In contrast to Howson et al. (10), however, we found that HLA-A*24 was the primary influence on ZnT8A prevalence rather than the linked locus identified by rs9258750. This suggests that a common mechanism may explain the reduced prevalence of ZnT8A and IA-2A. "
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