Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials

Aims/hypothesis: We investigated whether screening for insulinoma- associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A). Methods: IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA⁺, GADA⁺ and/or IA-2A⁺ siblings or offspring (+ (n = 97), 14% (n = 59) IA-2βA⁺ and 20% (n = 80) ZnT8A⁺. IA-2βA and ZnT8A were significantly (p <0.001) associated with IA-2A and prediabetes (n = 86); in IA-2A^- first-degree relatives (n = 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p <0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n = 409 to n = 246 (40%) with minor loss in the number of prediabetic IA-2A⁺ or ZnT8A⁺ first-degree relatives identified (n = 3). Conclusions/interpretation: IA-2A⁺ and/or ZnT8A⁺ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.