Multiple and High‐Titer Single Autoantibodies in Schoolchildren Reflecting the Genetic Predisposition for Type 1 Diabetes

Abstract

The study aimed to compare the HLA specificities of AAb-positive healthy schoolchildren with those of patients with type 1 diabetes (T1D). HLA-DRB1 and DQB1 alleles were determined in 178 AAb-positive and 339 AAb-negative schoolchildren aged 6-17 years without first-degree relatives with T1D and in 274 patients with T1D. AAbs against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by (125)I-antigen binding, and islet cell cytoplasmic antibodies (ICAs) immunohistochemically. Here, 82.6% (147/178) of AAb-positive schoolchildren had single AAbs and 17.4% (31/178) had multiple AAbs. In both groups, GADA occurred with highest and IAA with lowest frequency. In children with single AAbs at levels between the 99th and 99.9th percentile, frequencies of the diabetes-associated DRB1 (*03, *04) and DQB1 (*02, *0302) alleles and the protective DRB1 (*15) and DQB1 (*0602) alleles did not differ from those of controls. In patients, the positive associations were confirmed for DRB1*04 (OR = 5.39) and DQB1*0302 (OR = 9.05), whereas DRB1*15 (OR = 0.05) and DQB1*0602 (OR = 0.06) were negative-associated (p < 0.001). The same association was found in schoolchildren with multiple AAbs for DRB1*04 (OR = 3.84), DQB1*0302 (OR = 4.95), and DRB1*15 (OR = 0.1; p < 0.001-0.014), and with high-titer single AAbs (>/=99.9th percentile), but none of them had DQB1*0602. The highest risk genotype DQB1*02/*0302 occurred in 36.5% of patients (OR = 21.07) and in 19.3% of children with multiple AAbs (OR = 8.8; p<0.001). It is concluded that probands with multiple and high-titer single AAbs in the general population have the same genetic predisposition for T1D as patients and are therefore at highest risk for the disease.

Predicting type 1 diabetes

“…The BABYDIAB study showed that the genetic risk factors found in children who developed multiple islet autoantibodies were absent in children who developed single islet autoantibodies [7,17]. Similarly, the Australian BabyDiab study found that HLA DR4 and DR3 were more prevalent in children who developed persistent multiple islet autoantibodies than in children who were transient or single antibody positive [35], and the Karlsburg schoolchildren study found children with multiple islet autoantibodies, but not those with single islet autoantibodies who had HLA allele frequencies that were similar to those found in T1DM [50]. Finally, high-affinity IAA was associated with high-risk HLA DR4 containing genotypes [27••].…”

Longitudinal Frequencies of Blood Leukocyte Subpopulations Differ between NOD and NOR Mice but Do Not Predict Diabetes in NOD Mice

“…Some of the findings in the NOD mice were similar to what is observed in man. The relationship between increased IAA and more diabetes development is reflected by the faster rate of progression in antibody children if they have an earlier seroconversion or have higher islet autoantibody titers [ 13 , 14 ]. Similar to NOD mice, although much less pronounced, girls with islet autoantibodies progress to diabetes faster than boys [ 13 ].…”

Natural History of Type 1 Diabetes

“…Similarly, the Australian BABYDIAB study found that HLA DR4-DQ8 and DR3-DQ2 were more prevalent in children who developed persistent multiple islet autoantibodies than in children who were transient or single antibody positive (21). The Karlsburg schoolchildren study found children with multiple islet autoantibodies, but not in subjects with single islet autoantibodiesthey had HLA allele frequencies that were similar to frequencies found in type 1 diabetes (38). Finally, high affinity IAAs are associated with high-risk HLA DR4-DQ8 containing genotypes (14), and most IA-2A-positive offspring with the HLA DR3-DQ2/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes immediately develop a broad antibody reactivity to multiple epitopes expressed in both IA-2 and IA-2␤ (19).…”