GADIA2-COMBI DETERMINATION AS FIRST-LINE SCREENING FOR IMPROVED PREDICTION OF TYPE-1 DIABETES IN RELATIVES

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensi tivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibod y (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile o f 105 nondiabetic control subjects, and results were confirmed by test ing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA(+)/IA2A(+), 44 G ADA(+)/IA2A(-), and 4 IA2A(+)/GADA(-)). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADI A2-combi assay as well as in the single test for GADA or IA2A. Twenty- four relatives progressed to IDDM within a median follow-up time of 5. 6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30 -73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P = 0.0001) and o n the presence of IA2A in addition to GADA (5-year risk: GADA(+)/IA2A( +), 47% [25-68]; GADA(+)/IA2A(-), 15% [2-28]; P = 0.006). In those wit h detectable antibodies, risk was not associated with age (less than o r equal to 15 vs. >15 years) or relation to proband (offspring, siblin g, parent). Relatives with GADIA2-combi antibodies >10 U and the addit ional presence of IAA had a slightly higher diabetes risk than relativ es without IAA (5-year: IAA(+), 46% [23-68]; IAA(-), 19% [6-32]; P = 0 .07). Furthermore, low first-phase insulin release after intravenous g lucose tolerance test was associated with risk in relatives with GADIA 2-combi antibodies (P = 0.01). These results indicate that the GADIA2- combi test is a valuable marker for first-line screening and risk asse ssment of type 1 diabetes in relatives. It can be used for venous as w ell as capillary blood samples.