| 20091020 |
De Grijse J, Asanghanwa M, Nouthe B, Albrecher N, Goubert P, Vermeulen I, Van Der Meeren S, Decochez K, Weets I, Keymeulen B, Lampasona V, Wenzlau J, Hutton JC, Pipeleers D, Gorus FK: 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. 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. |
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