Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children

The relationships between genetic markers and disease-associated autoantibo dies were studied in an unselected population of 701 siblings of children w ith type 1 diabetes, and the predictive characteristics of these markers ov er a period of 9 years mere determined. Increased prevalences of all the an tibodies were closely associated with HLA identity to the index case, the D R4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 geno type. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*0 2 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles wer e characterized by lower frequencies of islet cell antibodies (ICA), antibo dies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to IFLA i dentity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences mere observed in the levels of IA-2A, GAD A, or insulin autoantibodies among siblings with different HLA risk markers . The DR2 or DQB1*0602-3 alleles mere not related to the levels of any anti body specificity. A combination of the genetic markers and autoantibodies i ncreased the positive predictive values of all autoantibodies substantially , which may have clinical implications when evaluating the risk of developi ng type 1 diabetes at the individual level or when recruiting high-risk ind ividuals for intervention trials. However, because such combinations also r esulted in reduced sensitivity, autoantibodies alone rather than in combina tion with genetic markers are recommended as the first-line screening in si blings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progr ess to disease.