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

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.