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

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.

FIG. 1.

Classification of patients according to country of birth of parents and grandparents. A total of 2,964 patients with autoimmune (≥1 autoantibody positive) T1D were included in this analysis. Non-Swedes (immigrants) accounted for 7% of patients, Swedes accounted for 73%, whereas 20% had mixed origins. Aab, autoantibody. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

Venn diagrams of islet autoantibodies. A: Frequencies and codetection (percent positive) of ZnT8A in A1: non-Swedes (n = 212) and A2: Swedes (n = 2,160). B: ZnT8A (≥1 ZnT8 autoantibodies) were detected in 4.7% of non-Swedes (B1) and 3.4% of Swedes (B2) who were negative for conventional autoantibodies. Unlike Swedes, non-Swedes develop ZnT8A more frequently with GAD65A rather than IA-2A. (A high-quality color representation of this figure is available in the online issue.)

FIG. 3.

Codetection of SLC30A8 with HLA-DQ genotypes. In non-Swedes, DQ2/X was detected more frequently with CC (**P = 0.009), and in Swedes, DQ8/X was detected more frequently with CT+TT (*P = 0.02) when compared with all other DQ genotypes. (A high-quality color representation of this figure is available in the online issue.)

FIG. 4.

ZnT8 epitopes in complex with HLA-DQ alleles. A: T-cell receptor view of the modeled structure of the T1D-susceptible HLA-DQ8 allele (A1*03:01-B1*03:02), in complex with the ZnT8 peptide 317–329, AHVATAASRDSQV (anchors underlined, polymorphic residue in italics). The ZnT8 peptide is shown in Van der Waals solid surface form (atom color code: carbon, green; oxygen, red; nitrogen, blue; hydrogen, white; sulfur, yellow), whereas the α1β1 domain of the HLA-DQ molecule is shown in Van der Waals surface form with atom charges (positive, blue; negative, red; neutral, gray, and with appropriate scales of gray for situations in between). The polymorphic residue 325Arg occupies pocket 7, for which it is eminently suited in this allele. B: T-cell receptor view of the modeled structure of the T1D-susceptible HLA-DQ2 allele (A1*05:01-B1*02:01), in complex with the ZnT8 peptide 317–329, AHVATAASWDSQV (anchors underlined, polymorphic residue in italics). Color conventions as in A. The polymorphic residue 325Trp occupies pocket 7, for which it is suited in this allele; HLA-DQ2 cannot tolerate arginine in any of its pockets. C: T-cell receptor view of the modeled structure of the T1D-susceptible HLA-DQ2 allele (A1*05:01-B1*02:01), in complex with the ZnT8 peptide 317–329, AHVATAASQDSQV (anchors underlined, polymorphic residue in italics). Color conventions as in A. The polymorphic residue 325Gln occupies pocket 7, for which it is well-suited in this allele. Note that there are slight rearrangements of both peptide residues and HLA-DQ residues because of the p7Trp→Gln substitution around the site of the substitution.