HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus

Abstract

Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n = 164), and a subset (n = 93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR+ was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system.

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese ? HLA antigens and organ-specific autoantibodies

“…This is in line with previous studies reporting that HLA-DR3 and HLA-DR4 were strongly associated with Type I diabetes among Caucasians [18][19][20], except that HLA-DRw9 found in Japanese patients was substituted for HLA-DR3 in Caucasian patients. The previous studies failed to show the association of HLADRw9 with Type 1 diabetes among Japanese [13,14].…”

“…Myasthenia gravis, which is an autoimmune disease directed to acetylcholine receptors of the neuromuscular junction, is similar in that its HLA-association varies among different ethnic groups; HLA-DR2 and DR3 in Caucasians [24], HLA-DR4 in Chinese [25], and HLADRw8 and DRw9 in Japanese [26]. These ethnic differences in HLA-association with Type I diabetes or myasthenia gravis might be derived from the difference in the distribution of HLA-DR antigens among the general population of the races; the prevalence of HLA-DR3 antigen is negligibly low not only in Type 1 diabetic patients but also in normal subjects, among Japanese as shown in the present study and previous studies [13,14,16], while it is considerably high even in the general population of Caucasians [18][19][20] and Chinese [23,25]. In this study, we found that HLA phenotype of DRw9 and HLA haplotype of Bw61-DRw9 were increased in Type 1 diabetic patients who had organspecific autoantibodies other than ICA; whereas HLA phenotype of DR4 and HLA haplotype of Bw54-DR4 were increased in those who did not have any autoantibodies.…”

“…One gene linked to HLA-DRw9 in Japanese or HLA-DR3 in Caucasians might be involved in the regulation of the immune system and another gene linked to HLA-DR4 in both races might be related to some other unknown functions. This is supported by the fact that the relative risk of HLADRw9/DR4 heterozygote or HLA-DR3/DR4 heterozygote is the highest among the related HLA-DR genotypes in Japanese or Caucasian Type 1 diabetic patients [18][19][20]28].…”

Diabetic nephropathy: Fault or destiny?

“…Since the risk of developing persistent proteinuria is significantly higher for diabetics who are 0-10 years old at diagnosis than in patients with a later onset of diabetes [13], it has been suggested that there may be different types of insulin dependent diabetes, one with an early onset which is associated with the antigens HLA-Dw4 and DR4 and another with onset around puberty and associated mainly with HLA-Dw3 and DR3 [14]. It is possible that the first type is associated with an early and total lack of endogenous insulin secretion and a predisposition to develop nephropathy, while the second type is associated with an insidious onset of B cell insufficiency and a lesser predisposition to develop nephropathy.…”

Islet cell antibodies ? Theoretical and practical implications

“…There may be a link between these immunopathological phenomena and the observation that Type 1 diabetes is associated with certain HLA-DR determinants, in particular HLA-DR3 and HLA-DR4 [4,5]. More than 90% of caucasoid children with Type 1 diabetes carry one or both of these specificities [5].…”