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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    ABSTRACT: The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual β-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data - future functional studies will be needed to clarify the relevance of these patterns.
    PLoS ONE 06/2013; 8(6):e64632. DOI:10.1371/journal.pone.0064632 · 3.23 Impact Factor
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    • "Individuals followed from birth to T1DM onset developed ZnT8A as early as 2 years of age with increasing levels and prevalence persisting to disease onset, which then decline after diagnosis of T1DM [43] [44]. The prevalence of ZnT8A is inversely related to the age at T1DM onset with the highest prevalence of 70% in the patients less than 10 years of age [42]. The same correlations also have been found with IA-2A and GADA. "
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is characterized by recognition of beta cell proteins as self-antigens, called autoantigens (AAgs), by patients' own CD4+ and CD8+ T cells and/or the products of self-reactive B cells, called autoantibodies. These AAgs are divided into two categories on the basis of beta-cell-specificity. The list of the targets associated with beta cell-specific AAgs is continuously growing. Many T1DM-associated AAgs are well characterized and have important clinical applications for disease prediction, diagnosis, and antigen-specific tolerance immunotherapy. Identification of T1DM-associated AAgs provides insight into the pathogenesis of T1DM and to understanding the clinical aspects of the disease. Since many excellent reviews have covered the previously identified T1DM-associated AAgs exhaustedly, here we only focus on several recently discovered T1DM-AAgs (PDX1, ZnT8, CHGA, and IAAP).
    American Journal of Translational Research 05/2013; 5(4):379-92. · 3.40 Impact Factor
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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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    ABSTRACT: The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA 2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes. Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis. We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset. HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate decarboxylase (GADA), IA-2, IA-2β and ZnT8 were analysed in samples collected from patients with recent-onset type 1 diabetes. After correction for age, gender, and HLA class II genotype, HLA-A*24 was shown to be a negative determinant of both IA-2A and ZnT8A. These effects were epitopespecific. Antibodies targeting the protein tyrosine phosphatase domains of IA-2 and IA-2β, but not the IA-2 juxta-membrane region were less common in patients carrying HLA-A*24 alleles. The prevalence of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those specific to arginine-325 was reduced in HLA*A24 positive patients. No associations were found between HLA-A*24 and IAA or GADA. Association of an HLA class I susceptibility allele with altered islet autoantibody phenotype at diagnosis suggests CD8 T-cell and/or natural killer cell mediated killing modulate humoral autoimmune responses.
    Diabetes 02/2013; 62(6). DOI:10.2337/db12-1468 · 8.10 Impact Factor
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