HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study

Abstract

Summary. Finnish Type l (insulin-dependent) diabeticfamilies were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type i diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type i diabetes at the population level.Key words: Type 1 (insulin-dependent) diabetes, restriction fragment length polymorphism, HLA-DQ, prediction of Type i diabetes, genetics.There is a strong relationship between HLA and Type 1 (insulin-dependent) diabetes mellitus, in that individuals having the HLA-DR3 and/or 4 antigen type run an increased risk of developing the disease. Determination of the Type i diabetes risk was previously based on serological and/or cellular HLA typing, but recent major breakthroughs in molecular biology have provided new tools for evaluation at the genomic level. Restriction fragment length polymorphism (RFLP) analysis in the HLA gene area has revealed several diabetes-associated polymorphisms [1, 2], suggesting that the susceptibility genes are located in the HLA-DQ region rather than the DR region. More recently it has been suggested that the amino acid at position 57 in the HLA-DQ beta-chain may play a critical role in determining predisposition to Type I diabetes. The presence of aspartic acid (Asp) in this position seems to provide protection against the development of the disease [3]. There are also results suggesting that Type i diabetes may be associated with an extended susceptibility haplotype [4,5] or with a combination of DR/DQ alleles [6,7] rather than with an isolated allele.The RFLP method was used here in order to detect polymorphisms implicated as genetic elements predisposing subjects to Type i diabetes. Use of an HLA-DQ betachain gene intron-specific probe revealed a hybridization pattern simple enough to be employed in screening surveys to identify subjects at risk of developing Type 1 diabetes.Our results support the role of the BamHI-12-kilobase and 4-kb fragments as susceptibility conferring markers for the disease [1,8] and show a striking difference between the diabetic patients and the control subjects in the frequency of 7.5/3.0-kb fragments reflecting a resistance to Type 1 diabetes. Furthermore, the trans-allelic genotypes indicate that the highest risk based...

A linkage study of 12 IDDM susceptibility loci in the Finnish population

“…In a genome scan of 356 UK ASPs, an LOD score of 3.2 was obtained with DR4/x stratified group, while an unstratified cohort gave an LOD score of 1.2, suggesting DR4-dependent HLA interaction at IDDM6 [13]. Our results are concordant with these findings since HLA-DQB1*0302 is found only in DR4 haplotype, and more than 90% of DR4 haplotypes found in diabetic children are HLA-DQB1*0302 positive [32].…”

Fourth International Onnela Workshop Immunology and Diet ? Towards the Prevention of Type 1 (insulin-dependent) Diabetes?

“…There are wide differences between the Type 1 diabetes risk carried by different Asp 57 negative haplotypes also in Western populations, but the combination of two different susceptibility markers in HLA-DQ area is a relatively specific marker for individuals at risk. This was also confirmed by us in restriction fragment length polymorphism studies of HLA-DQ beta-chain in Northern Finland, in which 51% of 61 Type i diabetes patients had a combination of 12 kb and 4 kb fragments compared to only 2% of 118 control subjects [3].…”

HLA types in women with cervical human papillomavirus (HPV) lesions prospectively followed up for 10 years

“…The frequencies of these 43 different HLA antigens in the 96 HPV patients were compared with frequencies of the HLA antigens in a Finnish control group. The latter is a local panel consisting of 188 individuals representing the normal distribution of HLA antigens in the Finnish population, as determined in previous studies of the prevalence of HLA in the community 32 .…”