HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families

Abstract

The role of HLA class II alleles in genetic predisposition to insulin dependent diabetes mellitus (IDDM) was examined by PCR/oligonucleotide probe typing of 42 Mexican-American IDDM families derived from Hispanic Caucasians and Native Americans. All high risk haplotypes (HLA-DR3 and DR4) were of European origin while the most strongly protective haplotype (DRB1*1402) was Native American. Of the 16 DR-DQ DR4 haplotypes identified, only those bearing DQB1*0302 conferred risk; the DRB1 allele, however, also markedly influenced IDDM risk. The general pattern of neutral and protective haplotypes indicates that the presence of Asp-57 in the HLA-DQ beta chain does not confer IDDM protection per se and indicates that both DRB1 and DQB1 influence IDDM susceptibility as well as protection.

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

“…[1][2][3][4] A large number of publications have established that particular combinations of alleles at HLA-DQB1, -DQA1, and -DRB1 show strong association with T1D. [5][6][7][8][9][10][11][12] The complex nature of this association is partly caused by the presence of multiple susceptible and protective HLA class II haplotypes, and may be modified by the presence of multiple other loci in the MHC region. 13,14 The haplotypes DRB1*0401-DQA1*0301-DQB1*0302 and DRB1*0301-DQA1*0501-DQB1*0201 have been found to be the major susceptible haplotypes in most populations, whereas DRB1*1501-DQA1*0102-DQB1* 0602 has been described to be protective in a dominant manner.…”

“…2 Many previous studies have measured the disease risk of DR-DQ haplo-and genotypes by odds ratios (ORs) and have categorized the haplo-or genotypes in terms of susceptibility, neutrality, and protection. 2,6,7,10,11 Inferences have also been made concerning the strength of susceptibility or protection, for example, DRB1*04 subtypes have been shown to display different ORs on an identical DQA1*0301-DQB1*0302 haplotype, with ranking 04054040140404404034 0406-8. 2,4,15 However, the presence of multiple diseaseassociated haplotypes complicates the analysis of the DR-DQ loci.…”

Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

“…[2][3][4][5] Here we compared the frequency of HLA-DR4 alleles in West Australian T1DM patients divided into COD and AOD groups (age at diagnosis o16 years for COD and X16 years for AOD) and control subjects. HLA-DRB1*0401 and -DRB1*0405 were significantly more common in COD and AOD than in controls.…”

“…Conversely, HLA-DRB1*0403, and in some studies -DRB1*0404, marked resistance. [2][3][4][5] Strong linkage disequilibrium between HLA-DR and -DQ complicates identification of critical class II alleles.…”

“…3 Alternatively, HLA-DR and -DQ alleles may both influence diabetogenesis, 4 possibly via trans-encoded heterodimers of -DQ proteins from some haplotypes, 1 or HLA-DRB1 may be the critical gene. 2 In addition to HLA class II alleles, other MHC genes are implicated in T1DM susceptibility.…”