Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study

  1. Åke Lernmark1
  2. for the Better Diabetes Diagnosis Study Group*
  1. 1Department of Clinical Sciences, Diabetes and Celiac Diseases, Lund University, Malmö, Sweden
  2. 2Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  3. 3Department of Pediatrics, Lund University, Lund, Sweden
  4. 4Department of Pediatrics, the Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
  5. 5Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden
  6. 6Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden
  7. 7Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institute, Stockholm, Sweden
  8. 8Division of Pediatrics and Diabetes Research Center, Linköping University Hospital, Linköping, Sweden
  9. 9Department of Woman and Child Health, Pediatric Endocrinology Unit, Karolinska Institute, Stockholm, Sweden
  10. 10Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden
  11. 11Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece
  1. Corresponding author: Ahmed J. Delli, ahmed.delli{at}med.lu.se.

Abstract

We examined whether zinc transporter 8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish patients due to different polymorphisms of SLC30A8, HLA-DQ, or both. Newly diagnosed autoimmune (≥1 islet autoantibody) type 1 diabetic patients (n = 2,964, <18 years, 55% male) were ascertained in the Better Diabetes Diagnosis study. Two subgroups were identified: Swedes (n = 2,160, 73%) and immigrants (non-Swedes; n = 212, 7%). Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%). ZnT8-RA (57 and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) than Swedes (46%). We tested whether this inconsistency was due to HLA-DQ as 2/X (2/2; 2/y; y is anything but 2 or 8), which was a major genotype in non-Swedes (40%) compared with Swedes (14%). In the non-Swedes only, 2/X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA. Molecular simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lack of tolerance to ZnT8-R. At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC30A8 CC (RR) genotypes.

Footnotes

  • Received December 5, 2011.
  • Accepted April 13, 2012.

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  1. Diabetes vol. 61 no. 10 2556-2564
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