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

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 less than 10(-5)) than HLA-identity (10% and 7%, respectively, p less than 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 less than 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 less than 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 less than 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).(ABSTRACT TRUNCATED AT 250 WORDS)