SNPs in the zinc transporter (ZnT8) and diagnosis of type 1 diabetes

摘要

Type 1 diabetes is an organ-specific autoimmune disease characterized by T-cell mediated destruction of pancreatic β-cells and the circulating autoantibodies to multiple islet autoantigens. During the past decade investigators have identified a series of islet autoantigens, including glutamic acid decarboxylase (GAD), insulinoma-associated antigen-2 (IA-2), and insulin. Recently, one of the zinc transporters, ZnT8, which is specifically expressed in the pancreatic β-cells, has identified as a major autoantigen in human type 1 diabetes. On the other hand, genome-wide association studies identified an association between a nonsynonymous variant in the ZnT8 gene (SLC30A8 rs13266634 ; Arg325Trp) and susceptibility to type 2 diabetes in various ethnic groups. We have investigated the association between humoral autoreactivity to ZnT8 and the SLC30A8 polymorphism and their clinical roles as an additional diagnostic marker of Japanese type 1 diabetes. In the present study, we found that ZnT8 autoantibodies recognize the cytoplasmic domain of the molecule and SLC30A8 polymorphism regulates humoral autoreactivity to ZnT8 in patients with type 1 diabetes. Furthermore, ZnT8 autoantibodies were detected in 60% of Japanese patients with type 1 diabetes and diagnostic sensitivity for combined analysis of autoantibodies to ZnT8, GAD, IA-2, and insulin was > 90%. These results indicate that variant residue at aa325 is a key determinant of humoral autoreactivity to ZnT8, SLC30A8 genotype is an important determinant of autoantibody specificity, and ZnT8 auoantibodies are an additional useful marker for Japanese type 1 diabetes.