INFLUENCE OF AGE ON THE ASSOCIATIONS AMONG INSULIN AUTOANTIBODIES, ISLET-CELL ANTIBODIES, AND HLA DQA1-ASTERISK-0301-DQB1-ASTERISK-0302 IN SIBLINGS OF PATIENTS WITH TYPE-1 (INSULIN-DEPENDENT) DIABETES-MELLITUS

In recent-onset type 1 (insulin-dependent) diabetes mellitus (IDDM), i nsulin autoantibodies (IAA) and islet cell antibodies (ICA) occur pref erentially in young (<10 yr) patients with the HLA DQA10301-DQB1*0302 risk haplotype. We investigated whether this association also exists in siblings of IDDM patients. In our group of 310 siblings, aged 0-39 yr, 6% were positive for IAA, 7% for ICA 12 Juvenile Diabetes Foundati on units (JDFU) or more, 5% for ICA 20 JDFU or more, and 2% for high t iter ICA (greater than or equal to 80 JDFU). The occurrence of IAA and ICA (greater than or equal to 20 JDFU) was significantly associated, with a preferential relationship to the HLA DQA10301-DQB1*0302 suscep tibility haplotype. In the present group of siblings, IAA and DQA1030 1-DQB10302 were significantly associated under age 10 yr (26% positiv ity for IAA vs. 4% in relatives without this haplotype). In this age g roup, IAA were more prevalent than (high titer) ICA (6%) in the presen ce of the haplotype. The association between (high titer) ICA and DQA1 0301-DQB1*0302 was not restricted to subjects under age 10 yr. High t iter ICA (n = 5) occurred exclusively in homozygotes for the latter ha plotype and in carriers of the heterozygous DQA10301-DQB1*0302/DQA1*0 501-DQB10201 high risk genotype, mostly under age 20 yr (four of five ). The preferential occurrence of IAA in DQA10301-DQB1*0302-positive siblings under age 10 yr was caused by their high prevalence (47%) in subjects with the heterozygous high risk genotype in this age group. A s in patients at onset, IAA and high titer ICA are preferentially asso ciated with the DQA10301-DQB1*0302 haplotype in siblings of IDDM pati ents, but, unlike at onset, these associations are observed with speci fic genotypes only and are more pronounced in subjects under age 10 yr for IAA only. Longitudinal analysis in first degree relatives and oth er normal controls carrying the DQA10301-DQB1*0302 haplotype should a ssess the hypothesis that IAA qualify as earlier predictive markers fo r IDDM than high titer ICA.