HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes

Abstract

Type 1 diabetes results from an autoimmune insulitis, associated with HLA class II alleles. The evidence about HLA allele association is not clear in patients diagnosed after 35 years of age. In this study we have analyzed HLA alleles of DQB1 and DRB1 genes by sequence specific primer (SSP)-PCR technique in adult patients with disease onset after 35 years of age. Two hundred and eighty-one patients were divided into three groups according to the insulin therapy, the level of C peptide (CP), and GAD antibodies (anti-GAD). Group 1 (type 1 diabetes in adults) was characterized by CP less than 200 pmol/L and anti-GAD more or less than 50 ng/mL (n = 80). All of them had insulin therapy within 6 months after diagnosis. Group 2 latent autoimmune diabetes mellitus in adults (LADA) was defined by a minimum 6-month-long phase after diagnosis without insulin therapy, and was characterized by CP more than 200 pmol/L and anti-GAD more than 50 ng/mL (n = 70). Group 3 (type 2 diabetes) was characterized by CP more than 200 pmol/L and anti-GAD less than 50 ng/mL (n = 131). None ever had insulin therapy. In group 1, there was increased frequency of DRB1*04 (45.0% vs. controls 14.1%, OR = 5.0, P < 0.0005) and DQB1*0302 alleles (43.3% vs. controls 11.1%, OR = 6.1, P < 0.00005). There was increased frequency of DRB1*03 and DQB1*0201, and decreased frequency of DQB1*0602 (3.3% vs. controls 20.2%), but it was not significant. In group 2, there was a significantly increased frequency of DRB1*03 only (50.0% vs. controls 21.2%, OR = 3.7, P < 0.05). Compared with children with type 1 diabetes and adults with type 2 diabetes (group 3), we conclude that the presence of predisposing DQB1 alleles in adults with type 1 diabetes decreases with the age, probably due to environmental factors. Only the DRB1*03, but not the DQB1 gene, becomes the main predisposing allele in LADA patients. These findings suggest that the presence of HLA-DQB1*0302 identifies patients at high risk of requiring insulin treatment. Type 1 diabetes mellitus (DM) in children or adults may have partly different immunogenetic etiopathogenesis than LADA.

Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype

“…The presence of a negative correlation between highrisk HLA genotypes and age of onset is in agreement with previous studies reporting a higher frequency of highrisk genotype in patients with an earlier age of onset [9,12,13,27], thus demonstrating an age-dependent HLA heterogeneity of T1DM. Komulainen observed that, in T1DM children younger than 2 years of age, the highrisk DQB1 * 0201/0302 genotype is more frequent than in older children, whereas the proportion of those carrying protective genotypes increase in the older age group (5-14.9 years) [18].…”

Latent autoimmune diabetes in adults (LADA) should be less latent

“…One study compared LADA with juvenileonset type 1 diabetes and found that the highest-risk DQ2/8 phenotype was not as frequent in LADA [13], consistent with the later onset of diabetes [20][21][22]. When LADA was compared with adult-onset type 1 diabetes [13,23] there were no consistent differences in class II allele frequency, suggesting that they have a similar genetic basis. Analysis of HLA class II and class I genes across the autoimmune diabetes spectrum encompassing juvenile-onset type 1 diabetes, adult-onset type 1 diabetes and LADA in different ethnic populations would further inform our understanding of the genetics of autoimmune diabetes presenting at different ages.…”

Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients

“…All examined subjects were of European descent and of the Czech nationality. We recruited about a half of the study subjects for the purpose of this study only; however, polymorphisms in selected loci and clinical parameters of some study subjects have been described previously [36-41]. For the purpose of calculating canonical correspondence analyses (CCA) and odds ratios (ORs), we matched the data obtained in the course of this study with previously published T1DM and control cohorts of subjects of European descent [32, 42] and compared them against Czech cohorts of HNF4A -, GCK - and HNF1A - maturity onset diabetes of the young (MODY) subjects [28].…”

“…In patients examined clinically prior to the year 2002, GADA was examined by the ELISA test from Roche Applied Science (Mannheim, Germany) with analytical sensitivity at 32 ng/mL and an arbitrary cutoff at 50 ng/mL [41]. Some of the measurements of islet cell autoantibodies have previously been analyzed in studies addressing other diabetes-associated genes [36-41, 58]. …”