Correlations between islet autoantibody specificity and theSLC30A8genotype withHLA-DQB1and metabolic control in new onset type 1 diabetes

Abstract

"Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes" ABSTRACTWe hypothesised that the correlation between autoantibody specificity for the ZnT8Arg325Trp isoforms and the type 2 diabetes associated rs13266634 may affect β-cell function at type 1 diabetes (T1D) onset. In order to study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titers of autoantibodies were correlated to genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual β-cell function. We replicated the correlation between rs13266634genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with GADA and IA-2A and correlated significantly with IA-2A prevalence (p<2e-16). No effect on AAD or IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p=0.016), which has not been shown previously.Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD<5 years (prevalence: p=0.004 and p=0.0001; titers: p=0.002 and p=0.001, respectively). The same trend was observed for IA-2A and ZnT8W, however the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, age at diagnosis, measures of β-cell function and HLA-DQB1 genotypes in T1D.

Relationship between ZnT8Ab, theSLC30A8gene and disease progression in children with newly diagnosed type 1 diabetes

“…Lampasona and co-workers have previously identified an additional 1.4% of autoantibody negative subjects as autoantibody positive when testing for ZnT8Ab in an adult-onset type 1 diabetes cohort [13]. In agreement with the previously reported 26% ZnT8Ab-positivity-rate among patients classified as autoantibody-negative [1] we find that 25% of the children classified as autoantibody negative in our study were ZnT8Ab positive, either for the shown to associate with T2D [7] and reduced first-phase insulin release in a glucosetolerant population, although this effect appeared to be associated with the CC genotype [8].…”

“…The insert was subcloned into the pTnT TM vector (Promega, Madison, USA) as described [12,13]. The ZnT8W variant was generated by site-directed mutagenesis and confirmed by DNA sequencing [12,13]. …”

Zinc transporter 8 autoantibodies in patients with type 1 diabetes from a multiethnic population and their first degree relatives

“…ZnT8 autoantibodies (ZnT8A) have been demonstrated to substantially overlap with the prevalence of IA2A, in particular (5). Mo reover, a significant correlation of the prevalence of ZnT8A and IA2A has been proven in T1D patients (6).…”

“…To date, there are three variants of ZnT8A detected in T1D patients, ZnT8RA (arginine), ZnT8WA (tryptophan) and ZnT8QA (glutamine) (8)(9)(10). The autoantibody specificity of ZnT8RA and ZnT8WA, respectively, has been shown to be determined by the rs13266634 genotype (5,6). In addition, the ZnT8RA variant was associated with the high risk HLA-DQB1*0302 genotypes (6).…”

Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3–6 years

“…Autoantibodies against GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q were measured as previously described in detail (15)(16)(17)(18)(19)(20). The diabetes autoantibody standardization program (DASP) performances were as follows: The intra-assay coefficient of variation for duplicates was 7% for GAD65A, 11% for IA-2A, 8% for ZnT8RA, 8% for ZnT8WA and 9% for…”