Association of particular HLA class II alleles, haplotypes and genotypes with susceptibility to IDDM in the Belgian population

Abstract

Summary Using a highly discriminatory DNA typing technique, based on the polymerase chain reaction and reverse dot blot hybridization, more refined results were obtained on the association of particular HLA class II alleles, haplotypes and genotypes with insulin-dependent diabetes mellitus in the Belgian population. The previously reported predisposing effect for the DRBI*0301 encoded DR3 serologic specificity was confirmed and could be assigned to the DRB3*0200 encoded DR52b serologic specificity. A second high risk haplotype, DRBI*0401-DQBI*0302 encoding the DR4-DQ8 serologic specificity, accounted for increased susceptibility both in the total insulin-dependent diabetic population and among DR4-positive patients. Moreover, we found that these DR4 associated DRB1 and DQB1 alleles act as independent risk factors. A possible role for the DPB1 locus can be rejected since the observed predisposing effect for DPBI*0202 probably occurred due to linkage disequilibrium of this allele with DRBI*0301. Particular extended haplotypes accounted for the decreased relative risk observed for the DR2, DR11 and DR13 serologic specificities. The highest relative risk was observed for those DQA1/DQB1 genotypes, allowing for the formation of 4SS (DQ0~Arg52+/DQflAsp57-) heterodimers. [Diabetologia (1994) 37: 808-817] Key words Insulin-dependent diabetes mellitus, HLA, class II, PCR, SSO typing.IDDM results from the autoimmune destruction of the pancreatic insulin-producing beta cells. Concordance rates for monozygotic twins (36 %), HLA-identical and -haplo-identical siblings (13 % and 4.5 %, respectively) suggest a multifactorial predisposition for this disease, the genetic factor being only partly determined by the HLA genes [1,2].

Distribution of HLA-DRB1 alleles in a mixed population with insulin-dependent diabetes mellitus from the Southeast of Brazil

“…There was an increased frequency of HLA-DRB1*03 and *04 among IDDM patients compared to the controls. These results are in agreement with data obtained for other Caucasian, African and Oriental groups (14)(15)(16). The strong IDDM risk conferred by DRB1*03/*04 heterozygosity in the Brazilian IDDM group is of the same order of magnitude as that observed in Caucasian patients (14,16).…”

IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity

“…High risk IDDM1 genotypes in Germany were similar to those of other Caucasian populations [12,13,14,15,16]. Consistent with the high T1D risk conferred by the DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 genotypes, a markedly increased risk of developing islet autoantibodies in the first years of life was observed for DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 offspring of parents with T1D.…”

A Genome-Wide Search for Linkage-Disequilibrium With Type 1 Diabetes in a Recent Genetically Isolated Population From the Netherlands

“…Only 33 patients (73.3%) carried the HLA-DR3 or DR4 allele, and only 8 (17.8%) were heterozygous for the DR3/DR4 allele. These frequencies were lower than expected frequencies of 90% (P Ͻ 0.00006) and 40% (P ϭ 0.017), which are found in most Caucasian populations (3,5), suggesting that other type 1 diabetes genes play a more important role in this population. The lower frequency of the high-risk HLA alleles makes this population very suitable for mapping of new type 1 diabetes genes.…”

“…Also, Ͼ90% of type 1 diabetes patients of European ancestry have at least one copy of the HLA-DR3 or DR4 allele, as compared with 45% in the general population. Almost 40% of type 1 diabetic patients have both alleles, although 3% is expected based on the frequency of the general population (3,4). Numerous studies have found several other genotypes within the HLA region to be associated with type 1 diabetes (referred to as IDDM1).…”