Zinc transporter type 8 autoantibodies (ZnT8A): prevalence and phenotypic associations in latent autoimmune diabetes patients and patients with adult onset type 1 diabetes

Abstract

Background and aims: Patients with type 1 diabetes have antibodies to ZnT8 protein is encoded by SLC30A8. The C-allele of the R325 W variant in SLC30A8 is associated with type 2 diabetes and reduced beta-cell function in non-diabetic subjects. Our aim was to assess the prevalence of ZnT8 autoantibodies (ZnT8A) in patients with adult-onset diabetes, and to characterize associations between ZnT8A and phenotype, as well as SLC30A8 and HLA-DQB1 genotypes. Methods: ZnT8A were analyzed in patients diagnosed with diabetes >35 years (type 1 diabetes: n = 274; Latent autoimmune diabetes in adults (LADA): n = 294). SLC30A8 R325 W (rs13266634) and HLA-DQB1 alleles were genotyped in all patients and 537 non-diabetic control subjects. Results: ZnT8A were significantly more prevalent in LADA (34.3%) compared to adult-onset type 1 diabetes (18.7%, p < 0.0001). Among the patients with adult-onset type 1 diabetes, ZnT8A were associated with shorter disease duration [4.4 (6.0) vs. 10.8 (11.2) years, p < 0.0001], whereas no such association was observed among patients with LADA. The SLC30A8 R325 W variant was associated with LADA with low GADA levels [SLC30A8 CC: OR (95% CI): 1.46 (1.00 – 2.13), p = 0.049], and reduced insulin secretion among the non-diabetic subjects and the patients with LADA. Conclusion: ZnT8A were more common and more persistent in patients with LADA compared to adult-onset type 1 diabetes, but their presence was not associated with specific phenotypic characteristics. The SLC30A8 CC genotype adds to the genetic heterogeneity of LADA linked to GADA reactivity.

Keywords::

• ZnT8A
• GADA
• LADA
• HLA-DQB1
• SLC30A8
• insulin secretion

Acknowledgements

Paula Kokko, Folkhälsan Research Center, is acknowledged for help with the genotyping and the Botnia Research Group and the FinnDiane Research group for recruiting and clinically studying the subjects. We thank Berta Davydova and Sinikka Helander for technical assistance in the ZnT8A assays.

Declaration of interest: The study was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, the Folkhalsan Research Foundation, the Finska Läkaresällskapet, the Ollqvist Foundation, Korsholm, Malax, Närpes and Vasa Health Care Centers and The Helsinki University Central Hospital. Per-Henrik Groop has received speaker honorariums from Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, MSD, Novartis, and Novo Nordisk, and is an advisory board member of Boehringer Ingelheim, Novartis, and Cebix. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.