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
- Ahmed J. Delli1⇓,
- Fariba Vaziri-Sani1,
- Bengt Lindblad2,
- Helena Elding-Larsson1,
- Annelie Carlsson3,
- Gun Forsander4,
- Sten A. Ivarsson1,
- Johnny Ludvigsson5,
- Ingrid Kockum6,
- Claude Marcus7,
- Ulf Samuelsson8,
- Eva Örtqvist9,
- Leif Groop10,
- George P. Bondinas11,
- George K. Papadopoulos11 and
- Åke Lernmark1
- for the Better Diabetes Diagnosis Study Group*
- 1Department of Clinical Sciences, Diabetes and Celiac Diseases, Lund University, Malmö, Sweden
- 2Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- 3Department of Pediatrics, Lund University, Lund, Sweden
- 4Department of Pediatrics, the Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
- 5Department of Clinical and Experimental Medicine, Division of Pediatrics, Linköping University, Linköping, Sweden
- 6Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden
- 7Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institute, Stockholm, Sweden
- 8Division of Pediatrics and Diabetes Research Center, Linköping University Hospital, Linköping, Sweden
- 9Department of Woman and Child Health, Pediatric Endocrinology Unit, Karolinska Institute, Stockholm, Sweden
- 10Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- 11Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece
- Corresponding author: Ahmed J. Delli, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1659/-/DC1.
*Members of the Better Diabetes Diagnosis Study Group are listed in the Supplementary Data online.
- Received December 5, 2011.
- Accepted April 13, 2012.
- © 2012 by the American Diabetes Association.
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