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Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes

Brorsson, Caroline; Vaziri Sani, Fariba LU ; Bergholdt, Regine; Eising, Stefanie; Ramelius, Anita LU ; Svensson, Jannet; Lernmark, Åke LU and Pociot, Flemming (2011) In Autoimmunity 44(2). p.107-114
Abstract
We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan... (More)
We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ZnT8, SLC30A8, autoantibody specificity, HLA-DQB1, beta-cell function
in
Autoimmunity
volume
44
issue
2
pages
107 - 114
publisher
Taylor & Francis
external identifiers
  • wos:000288236200005
  • scopus:79551557612
ISSN
0891-6934
DOI
10.3109/08916934.2010.509120
language
English
LU publication?
yes
id
ce6be05e-462a-4a80-99cb-b6530098eda1 (old id 1868672)
date added to LUP
2011-04-04 12:41:38
date last changed
2017-10-22 04:20:06
@article{ce6be05e-462a-4a80-99cb-b6530098eda1,
  abstract     = {We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p &lt; 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD &lt; 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.},
  author       = {Brorsson, Caroline and Vaziri Sani, Fariba and Bergholdt, Regine and Eising, Stefanie and Ramelius, Anita and Svensson, Jannet and Lernmark, Åke and Pociot, Flemming},
  issn         = {0891-6934},
  keyword      = {ZnT8,SLC30A8,autoantibody specificity,HLA-DQB1,beta-cell function},
  language     = {eng},
  number       = {2},
  pages        = {107--114},
  publisher    = {Taylor & Francis},
  series       = {Autoimmunity},
  title        = {Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes},
  url          = {http://dx.doi.org/10.3109/08916934.2010.509120},
  volume       = {44},
  year         = {2011},
}