Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) 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

Diabetologia. 2010 Mar;53(3):517-24. doi: 10.1007/s00125-009-1618-y. Epub 2009 Nov 29.


Aims/hypothesis: We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2beta) autoantibodies (IA-2betaA) 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-2betaA 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 (<40 years) of type 1 diabetic patients consecutively recruited by the Belgian Diabetes Registry. The median (interquartile range) age of the first-degree relatives was 12 (6-19) years.

Results: Of the first-degree relatives, 24% were IA-2A(+) (n = 97), 14% (n = 59) IA-2betaA(+) and 20% (n = 80) ZnT8A(+). IA-2betaA 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-2betaA 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / chemistry
  • Cation Transport Proteins / biosynthesis*
  • Child
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Family Health
  • Female
  • HLA-DQ Antigens / metabolism
  • Humans
  • Insulin / metabolism
  • Male
  • Predictive Value of Tests
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / biosynthesis*
  • Zinc / chemistry


  • Autoantibodies
  • Cation Transport Proteins
  • HLA-DQ Antigens
  • Insulin
  • SLC30A2 protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Zinc