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IDDM1 and Multiple Family History of Type 1 Diabetes Combine to Identify Neonates at High Risk for Type 1 Diabetes

¹ Immunology of Diabetes Unit, Istituto Scientifico San Raffaele, Milan, Italy
² Diabetes Research Institute and Academic Hospital Schwabing, Munich, Germany

Address correspondence and reprint requests to Prof. Dr. Anette-G. Ziegler, Institut für Diabetesforschung, Kölner Platz 1, D-80804 München, Germany. E-mail: anziegler{at}lrz.uni-muenchen.de

OBJECTIVE—Children of affected probands are at increased risk for type 1 diabetes. The objective of this study was to determine and stratify the risk for islet autoimmunity and childhood diabetes in newborn offspring of affected parents using family history and HLA genetic markers.

RESEARCH DESIGN AND METHODS—Antibodies to islet autoantigens were measured at ages 9 months, 2 years, 5 years, and 8 years in 1,610 offspring of parents with type 1 diabetes participating in the German BABYDIAB study. HLA DR and DQ genetic typing was performed. Family history of type 1 diabetes was obtained from questionnaires.

RESULTS—Extensive family history of type 1 diabetes and HLA DR/DQ genotyping were associated with islet autoantibody and diabetes risks. Significant contributions to the child’s risk for developing islet autoantibodies and type 1 diabetes were conferred by a multiple first-degree family history of type 1 diabetes (two parents or one parent and a sibling; adjusted hazard [HR] ratio, 6.2 for multiple islet autoantibodies and 7.8 for type 1 diabetes), high-risk HLA genotypes (adjusted HR, 11 and 10.9), and moderate-risk HLA genotypes (adjusted HR, 6.3 and 4.3) in a multivariate analysis. Combining these factors stratified the risk for islet autoantibodies from 1 to 46% and for type 1 diabetes from 0 to 19.5% by 5 years of age.

CONCLUSIONS—Risk of childhood diabetes in affected families can be stratified using a combination of genetic and family history markers very early in life.

Abbreviations: GADA, GAD antibody • IAA, insulin autoantibody • IA2A, IA2 antibody • OGTT, oral glucose tolerance test • WHO, World Health Organization

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