Young age and HLA markers enhance the risk of progression to type 1 diabetes in antibody-positive siblings of diabetic children

The contribution of autoantibodies, HLA markers and age to long-term estima tes of risk of type 1 diabetes were examined after a median of 11 years (ra nge 7.5-14) during the follow-up in a cohort of 234 siblings (aged 2-29 yea rs) of French children with recent-onset type 1 diabetes, of whom 12 (5.1%) developed diabetes. We evaluated islet cell antibodies (ICA) by indirect i mmunofluorescence and autoantibodies to insulin (IAA), to the 65 kDa isofor m of glutamic acid decarboxylase (GADA) and to the IA-2 protein (IA-2A) by radioligand assay in sequential serum samples. Among the 234 siblings of ty pe 1 diabetic patients screened, 27 were positive for at least one antibody , 11 of whom progressed to develop type 1 diabetes during the follow-up (se nsitivity, 92%, predictive value, 41%). Among the four antibodies tested in dividually, ICA had, the highest sensitivity (83%) but a poor predictive va lue (59%) and IA-2A the highest predictive value (70%). IAA and GADA both e xhibited poor sensitivity and predictive value. Combinations of antibodies achieved better predictive values than antibodies tested individually. Sati sfactory predictive values were obtained for the combination of GADA with I A-2A 1:83%), for any combination of at least two antibodies other than ICA (70%) and for the combination of ICA with at least one other antibody (69%) . The risk estimates were highest in the presence of three or four antibodi es, whether comprising ICA or not, but with a concomitant loss of sensitivi ty. For most antibody combinations, cumulative risks showed progression fro m approximately 50% after 5 years to 100% after 13 years. HLA-DR3/4 was sig nificantly more frequent in siblings developing type 1 diabetes than in non -diabetic siblings (9/12 vs. 39/217, relative risk (RR)=14, P less than or equal to 0.0001). The predictive value of HLA-DR3/4 was low (19%); however, taking into account the presence of HLA-DR3/4 in subjects who were positiv e for more than one antibody resulted in a higher predictive value (67%, vs . 20% in non-DR3/4 subjects, P less than or equal to 0.02). In addition, si blings developing diabetes were younger at entry than those who did not (me an =7.5 +/- 1.23 vs. 12.5 +/- 0.39 years, respectively; P less than or equa l to 0.01). Ten of 12 were aged less than 10 years compared with 106/222 no n-diabetic siblings (RR = 5.4, P less than or equal to 0.03). Moreover, you nger age was associated with a more rapid development of type 1 diabetes. I n conclusion, our results show that the combination of IAA, GADA and IA-2A autoantibodies in sequential serum samples is satisfactory for the identifi cation of subjects at risk of developing type 1 diabetes. Additional factor s such as younger age and HLA-DR3/4 as markers of progression to disease ma y contribute to more efficient prediction in antibody positive subjects. (C ) 1998 Academic Press.