Life table analysis of the risk of Type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers

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Abstract
To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2–29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p −5) than HLA-identity (10% and 7%, respectively, p p −7). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4+ subjects had the highest risk (70% after 8 years, predictive value 58%, p −7) compared with islet cell antibody-positive DR3,4− (37% and 20%, respectively) and islet cell antibody-negative DR3,4+ (5% and 3.6%, respectively). Furthermore, islet cell antibody-positive DR3,4+ siblings progressed to diabetes at a younger age (risk 84% by age 22 years vs 20% in islet cell antibody-positive DR3,4− siblings, p <0.005). Siblings with moderate islet cell antibody levels who carry the DR3,4 antigens have been identified as a subgroup with increased risk and more rapid progression to Type 1 diabetes.