Immunogenetics of Childhood Type 1 Diabetes in Immigrant Patients in Sweden. Migration Studies on Type 1 Diabetes

Research output: ThesisDoctoral Thesis (compilation)

Abstract

This thesis examined whether the offspring of immigrants (non-Swedes) to Sweden are at increased risk of Type 1 Diabetes (T1D) when they are born or live in Sweden. It also evaluated if their T1D and T2D-related genes differed from Swedish patients and whether this genetic heritage determined the types and existence of islet autoantibodies at time of diagnosis and affected the classification of diabetes.
A total of 3451 (55% males) newly diagnosed T1D patients (<18 y) were recruited from the Better Diabetes Diagnosis (BDD) study. We calculated the “patients/105/y” rate of confirmed T1D, which was 14 (95%CI: 13-15) among non-Swedes (8% of total) compared to 22 (95% CI: 21-23) for Swedes (66%). The rate for non-Swedes was at least 2 times higher than the mean incidence rates for countries of parents’ origins. Non-Swedes had predominately GAD65A (64%) in association with DQ2, which prevailed in the non-Swedes (34%, OR=1.5) compared to Swedes (15%). The Swedes had more multiple (>=2) autoantibodies and IA-2A in association with the dominant DQ8 and 2/8. The ZnT8-WA (38%) found less in non-Swedes compared to Swedes (50%), consistent with lower frequency in the non-Swedes (37%) of the SLC30A8 CT+TT than in Swedes (54%). The ZnT8-RA (57% and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) compared to Swedes (46%). In non-Swedes only, the prevailing DQ2/X (40%) compared to Swedes (14%) was negatively associated with ZnT8-WA (p=0.008) and ZnT8-QA (p=0.03) but not ZnT8-RA (p=0.26). Molecular simulation showed non-binding of the relevant ZnT8R peptide to DQ2 explaining in part the possible lack of tolerance to ZnT8-R by DQ2. The DQ8 and DQ6.4 had stronger binding epitopes outside the polymorphic site at amino acid position 325. The INS-SNP rs689 A/A genotype contributed T1D risk in non-Swedes (65%), though less than Swedes (72%). IAA were predicted by A/A (OR=3.5) but negatively associated with increasing age at diagnosis (OR=0.1) and HLA-DQ2 regardless of ethnic background (OR=0.6) explaining, in addition to INS T/T, the lower IAA in non-Swedes. In the
Swedes only, IAA were associated with DQ2/8 (40%) and 8/x (32%), which were also stronger predictors of IAA at a younger age than INS genotypes. Non-Swedes were further subdivided into non-Europeans (n=148, 63%) and European-descent (n=86, 37%). Non-European had less T1D risk genes (HLA DQ and PTPN22) and more T2D risk genes (SLC30A8 and FTO genes), therefore they were more prone to be autoantibody-negative (11% compared to 8% in Europeans and 6% in Swedes)and had less multiple autoantibodies (64%% compared to 81% in Europeans and 79% in Swedes).
Our data suggest that immigrants from low incidence countries (80% were born in Sweden), especially non-Europeans, are exposed to higher T1D in Sweden, because their genetic heritage affected by the Swedish environment. Non-European immigrants develop T1D in Sweden with lesser T1D-related genes but more T2D-related genes and less islet autoantibodies when compared to Europeans and native Swedes.

Details

Authors
  • Ahmed Delli
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Medicine

Keywords

  • Diabetes, Type 1 Diabetes, Childhood, Human Leukocyte Antigen (HLA), Islet autoantibodies, Zinc Transporter 8 (ZnT8), Islet antigen (IA2-), Glutamic Acid Decarboxylase 65 (GAD65, Insulin, Migration.
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2012 Feb 17
Publisher
  • Department of Clinical Sciences, Lund University
Print ISBNs978-91-86871-76-5
Publication statusPublished - 2012
Publication categoryResearch

Bibliographic note

Defence details Date: 2012-02-17 Time: 13:00 Place: Jubileumsaulan, entrance 59, Skåne University Hospital (SUS), Malmö. External reviewer(s) Name: Joner, Geir Title: Professor Affiliation: University of Oslo, Norway ---

Related research output

Delli, A., Vaziri Sani, F., Lindblad, B., Helena Larsson, Annelie Carlsson, Forsander, G., Sten Ivarsson, Ludvigsson, J., Kockum, I., Marcus, C., Samuelsson, U., Ortqvist, E., Leif Groop, Bondinas, G. P., Papadopoulos, G. K. & Åke Lernmark, 2012, In : Diabetes. 61, 10, p. 2556-2564

Research output: Contribution to journalArticle

Delli, A., Lindblad, B., Annelie Carlsson, Forsander, G., Sten Ivarsson, Ludvigsson, J., Marcus, C. & Åke Lernmark, 2010, In : Pediatric Diabetes. Apr 8, p. 513-520

Research output: Contribution to journalArticle

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