LIFE TABLE ANALYSIS OF THE RISK OF TYPE-1 (INSULIN-DEPENDENT) DIABETES-MELLITUS IN SIBLINGS ACCORDING TO ISLET CELL ANTIBODIES AND HLA MARKERS - AN 8-YEAR PROSPECTIVE-STUDY

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 < 10(-5)) than HLA-identity (10 % and 7 %, respectively, p < 0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4 %, 3 % and 4.4 %, respectively, NS). C4BQO also conferred significant risk (11 % vs 3 % in non-C4BQO siblings, p < 0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7 % for HLA-identity, 9 % for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41 %, risk 56 % after 8 years, p < 10(-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 < 10(-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.